Immunomodulating urea azalides

ABSTRACT

Defined herein are immunomodulating Formula (1) compounds wherein R, R0, R1, R2,R3 and W are as defined herein, stereoisomers thereof, and pharmaceutically acceptable salts thereof; and compositions comprising said compounds. The invention also includes methods for treating an inflammatory and/or immunological disease or disorder in an animal by administering a therapeutically effective amount of a Formula (1) compound, stereoisomer thereof, and a pharmaceutically acceptable salt thereof; or use of said compound of Formula (1) to prepare a medicament for treating an inflammatory and/or immunological disease or disorder in an animal.

FIELD OF THE INVENTION

Defined herein are anti-inflammatory and immune-modulating compounds;non-antibacterial, anti-inflammatory and immune-modulating compounds;stereoisomers thereof, and pharmaceutically acceptable salts thereof.The invention includes the respective 13-membered macrolide ringcompounds that are in equilibrium with the 15-membered macrolide ringcompounds. The invention also includes pharmaceutical compositionscomprising a compound of the invention and methods for treating aninflammatory and/or immunological disease or disorder in an animal. Thecompounds of the invention are azalides.

BACKGROUND OF THE INVENTION

Macrolides are antibacterial compounds that consist of a largemacrocyclic lactone ring containing 12 to 16 atoms, which are attached,via glycosidic bonds, to at least one or two deoxy sugars. Azalides area class of macrolide wherein the lactone ring contains a nitrogen atom.Draxxin© is a semi-synthetic macrolide (azalide) antibiotic that is soldas a ready to use sterile parenteral preparation containingtulathromycin. The preparation consists of an equilibrated mixture oftwo isomeric forms of tulathromycin in a 9:1 (Tula-A:Tula-B) ratio.Tula-A is a 15-membered lactone ring structure wherein Tula-B is a13-membered lactone ring structure. Equilibrium is pH and timedependent. Tulathromycin is marketed for bovine respiratory disease(BRD) and swine respiratory disease (SRD) under the tradename, Draxxin©.

Macrolides are known for inhibiting protein synthesis in bacteria (Grampositive and Gram negative) by reversibly binding to the P site of the50S unit of the ribosome. They tend to be bacteriostatic and may bebactericidal against some pathogens. Their activity against theGram-negative pathogens of BRD and ability to concentrate in lung tissuemake them an excellent therapeutic. They are the first-line treatmentagainst BRD and are also used to treat respiratory infections in humans.

Known macrolide antibiotics include, for example, erythromycin,tilmicosin, azithromycin, clarithromycin, gamithromycin, fidaxomicin,roxithromycin, tulathromycin and others. In addition, some macrolideshave been shown to have anti-inflammatory and immune-modulatingproperties. For example, azithromycin, a broad-spectrum antibiotic,suppresses interleukin 12p40 expression in lipopolysaccharide (LPS) andinterferon-gamma stimulated macrophages and attenuates LPS inducedinduction of CXCL8 (IL-8) and GM-CSF from primary bronchial epithelialcells; and in epithelial cells, interactions with phospholipids andErk1/2, are followed by down-regulation of transcription factors AP-1,NFκB, inflammatory cytokines and mucin release following LPSstimulation. US2016-0031925 describes certain azithromycin analoguesthat are immune-modulating but have been modified to reduce or eliminatethe antibiotic effect. Clarithromycin has an immunomodulatory effect onERJ-mediated inflammation induced by Pseudomonas aeruginosa flagellin.Erythromycin inhibits interleukin-6 and interleukin-8 expression andpromotes apoptosis of activated human neutrophils in vitro. Tilmicosinmodulates COX-2 and iNOS gene expression and production of cytokines inLPS-stimulated macrophages and monocytes. Roxithromycin down-regulatesTh2 chemokine production by keratinocytes and chemokine receptorexpression on Th2 cells. Tulathromycin promotes apoptosis anddown-regulates pro-inflammatory mediators like leukotriene B4 and CXCL8;and induces production of anti-inflammatory and pro-resolving lipidlipoxin A4. Research findings demonstrate that these anti-bacterialmacrolides modulate certain excessive immune responses which in turncascade into certain anti-inflammatory benefits.

Inflammation and pro-inflammatory mediators negatively affect productionin the food animal industry by reducing growth, feed and water intake,reproduction, milk production and metabolic health. Increased clinicaluse of macrolide antibiotics is linked with an increase in pneumococcalmacrolide resistance and resistance in BRD pathogens. Recent concerns byglobal governmental agencies and the general public relative to use ofantibiotics in food producing animals (e.g., cattle and swine) has beenthought to lead to cross resistance to human pathogens. Bovinerespiratory disease (BRD) remains a major problem in modern day cattleproduction and judicious management is vitally important for both animalwelfare and human food safety. In fact, Mannheimia haemolytica is aprinciple bacterium isolated from respiratory disease in feedlot cattleand is a significant component of enzootic pneumonia in neonatal calves.One of the hallmarks of BRD is a heightened inflammatory response in thehost that promotes progression to the full BRD complex. Inhibiting orreversing the inflammation in the host has the ability to prevent orcontrol the development of BRD in cattle and other inflammatory diseasesor disorders in animals. Therefore, there is an unmet desire to developa new anti-inflammatory and immune-modulating agent that lacks theantibacterial effects of the known macrolides. The compounds of theinvention have been shown to be non-antibacterial in multiple bacterialspecies and possess upwards of 5-20 times greater immune-modulatingactivity at lower dosages than current macrolides (e.g., azithromycin,erythromycin and tulathromycin). Therefore, the compounds can be used tocontrol or prevent the onset of a bacterial infection or viral infectionwhich is enabled by an inflammatory and/or immune response due to astressful event or other environmental factor(s) thereby preventing ormitigating the pathobiological cascade from advancing to the fulldisease complex. The compounds of the invention presented herein arenon-antibiotic, anti-inflammatory and immune-modulating macrolides forthe reduction of an inflammatory state in animals with the potential forreducing the use of antibiotics in animals.

SUMMARY OF THE INVENTION

In one aspect of the invention, is an anti-inflammatory andimmune-modulating Formula (1) azalide compound; or a non-antibacterial,anti-inflammatory and immune-modulating Formula (1) azalide compound;stereoisomers thereof, and pharmaceutically acceptable salts thereof,

wherein W is H or Formula (A)

wherein X is —R^(a), —R^(c)NR⁵R⁶, —R^(c)OR⁷, —R^(c)SR⁷, —R^(c)N₃,—R^(c)CN or —R^(c)X′;

X is F, Cl, I or Br;

R is H, C₁-C₃alkyl, —C(O)NR^(a)R^(d) or —C(O)OR⁸;R^(a), R^(b), R⁰ and R¹ are each independently H or C₁-C₆alkyl;or R¹ is benzyl optionally substituted with at least one R⁹ substituent;or R¹ is —CH₂Het wherein Het is a 5-6 membered heteroaryl ringcontaining at least one heteroatom selected from N, S and O; and whereinthe heteroaryl ring is optionally substituted with at least one R⁹substituent;R^(c) is C₁-C₄alkyl;R^(d) is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, or phenyl optionallysubstituted with C₁-C₃alkyl, C₁-C₃alkoxy, halogen, cyano, hydroxy,amino, —NHCH₃, —N(CH₃)₂, C₁-C₃haloalkyl or C₁-C₃haloalkoxy;R² and R³ are each independently is H, C₁-C₆alkyl, R^(c)NR^(a)R^(b),C₀-C₃alkylC₃-C₆cycloalkyl, C₀-C₃alkylaryl, C₀-C₃alkylheterocycle whereinthe heterocycle is a 5-6 membered saturated or partially saturatedheterocycle ring; or C₀-C₃alkylheteroaryl wherein the heteroaryl is a5-6 membered heteroaryl ring; wherein the heterocycle ring and theheteroaryl ring each contain at least one heteroatom selected from N, Oand S; and wherein the cycloalkyl, aryl, heterocyclic and heteroarylrings are each optionally substituted with at least one R⁹ substituent;or R² and R³ taken together with the nitrogen atom to which they areattached form Ring A, a 4-8 membered heterocyclic ring or a 5-memberedheteroaryl ring, each optionally containing at least one additionalheteroatom selected from N, O and S; each ring is optionally substitutedwith at least one R¹⁰ substituent; and wherein each ring is optionallyfused with Y;R⁵ and R⁶ are each independently selected from H; C₁-C₆alkyl orC₁-C₆alkoxy each optionally substituted with at least one hydroxy; orcyano, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸,—C(O)R^(c)NR^(a)R^(b), —C(O)OR^(c)R⁸, —C(O)ONR^(a)R^(b),—R^(c)NR^(a)C(O)R⁸, —R^(c)C(O)OH, —R^(c)C(O)NR^(a)R^(b),—R^(c)NR^(a)C(O)H, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸, —S(O)_(p)R⁸NR^(a)R^(b), —R^(c)S(O)_(p)NR^(a)R^(b) or—R^(c)NR^(a)S(O)_(p)R⁸; or C₀-C₄alkylaryl, C₀-C₄alkylC₃-C₆cycloalkyl,C₀-C₄alkylheterocycle or C₀-C₄alkylheteroaryl, wherein the heterocycleand heteroaryl rings are each a 5-6 membered monocyclic ring or a 9-10membered fused ring, each containing at least one heteroatom selectedfrom the group consisting of N, O and S; and wherein the aryl,cycloalkyl, heterocycle and heteroaryl rings are optionally substitutedwith at least one R¹⁰ substituent;or R⁵ and R⁶ taken together with the nitrogen atom to which they areattached form Ring B, a 4-8 membered heterocyclic ring or a 5 memberedheteroaryl ring, each optionally containing at least one additionalheteroatom selected from N, O and S; each ring is optionally substitutedwith at least one R⁹ substituent; and wherein each ring is optionallyfused with Y;R⁷ is H, C₁-C₆alkyl, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—R^(c)S(O)_(p)R^(a), —R^(c)NR^(a)C(O)R^(b), —R^(c)C(O)NR^(a)R^(b),—R^(c)NR^(a)C(O)NR^(a)R^(b) or —R^(c)NR^(a)C(O)OR^(b);R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₀-C₄alkylC₃-C₆cycloalkyl,—NR^(a)R^(b), phenyl, a 5-6 membered heterocyclic ring containing atleast one heteroatom selected from N, O and S, or a 5-6 memberedheteroaryl ring containing at least one heteroatom selected from N, O,and S; and wherein the cycloalkyl, phenyl, heterocycle and heteroarylare each optionally substituted with at least one substituent selectedfrom C₁-C₄alkyl, halogen, C₁-C₄alkoxy, C₁-C₄haloalkyl andC₁-C₄haloalkoxy;R⁹ is independently selected from the group consisting of C₁-C₆alkyl,C₁-C₆alkoxy, C₀-C₄alkylC₃-C₆cycloalkyl, halogen, oxo, hydroxy, cyano,—NR^(a)R^(b), C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —S(O)_(p)R⁸, phenyl, anda 5-6 membered monocyclic heterocyclic or heteroaryl ring eachcontaining at least one heteroatom selected from the group consisting ofN, O and S;R¹⁰ is independently selected from the group consisting of C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₀-C₄alkylC₃-C₆cycloalkyl,halogen, —NR^(a)R^(b), —S(O)_(p)R⁸, nitro, oxo, cyano, —C(O)H, —C(O)R⁸,—C(O)OR^(a), —OC(O)OR^(a), —NHR^(c)C(O)R^(a), —C(O)NR^(a)R^(b), hydroxy,a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 9-10membered fused heteroaryl ring wherein each heterocyclic and heteroarylring each contain at least one heteroatom selected from the groupconsisting of N, O and S; and phenyl; and wherein the phenyl,heterocyclic and heteroaryl ring are each optionally substituted with atleast one R⁹ substituent;Y is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl,triazolyl, isothiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl,furanyl, indolyl, benzothienyl or naphthyl; p is the integer 0, 1, or 2;stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, the composition further comprises a pharmaceuticallyacceptable carrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect of the method, the inflammatory response is due to abacterial, viral, or fungal infection, stress, and/or an environmentalfactor. In another aspect of the method, the method of treating orpreventing an inflammatory response in an animal prevents or mitigatesthe progression of a respiratory disease or disorder. In another aspectof the method, the animal is livestock. In another aspect of the method,the respiratory disease or disorder is bovine respiratory disease orswine respiratory disease. In another aspect of the method, the methodof treating or preventing an inflammatory response in an animal downregulates TNFα and IL-6 in the animal.

In another aspect, is the use of a Formula (1) compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof; to prepare amedicament for treating or preventing an inflammatory response in ananimal wherein the inflammatory response is due to a bacterial, viral,or fungal infection, stress, and/or an environmental factor. In anotheraspect of the use, the use of the medicament for treating or andpreventing an inflammatory response in the animal prevents or mitigatesthe progression of a respiratory disease or disorder. In another aspectof the use, the animal is livestock. In another aspect of the use, therespiratory disease or disorder is bovine respiratory disease or swinerespiratory disease. In another aspect of the use, the use ofadministering the medicament to the animal to treat or prevent aninflammatory response in the animal down regulates TNFα and IL-6 in theanimal.

In another aspect of the invention, R^(a) and R^(b) are eachindependently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl ort-butyl. In another aspect, R^(a) and R^(b) are each independently H,methyl, ethyl, propyl or isopropyl. In another aspect, R^(a) and R^(b)are each independently H, methyl, ethyl or propyl. In another aspect,R^(a) and R^(b) are each independently H or methyl.

In another aspect of the invention, R^(c) is methyl, ethyl, propyl,isopropyl, n-butyl, or t-butyl. In another aspect of the invention,R^(c) is methyl, ethyl, propyl, isopropyl, or t-butyl. In another aspectof the invention, R^(c) is methyl, ethyl, propyl, or isopropyl. Inanother aspect of the invention, R^(c) is methyl, ethyl or propyl. Inanother aspect, R^(c) is methyl. In another aspect, R^(c) is ethyl. Inanother aspect, R^(c) is propyl.

In another aspect of the invention, R^(d) is C₁-C₆alkyl, C₃-C₆cycloalkylor phenyl optionally substituted with C₁-C₃alkyl, C₁-C₃alkoxy, halogen,cyano, hydroxy, amino, —NHCH₃, —N(CH₃)₂, C₁-C₃haloalkyl orC₁-C₃haloalkoxy. In another aspect, R^(d) is C₁-C₆alkyl, C₃-C₆cycloalkylor phenyl optionally substituted with C₁-C₃alkyl, C₁-C₃alkoxy, halogen,cyano, hydroxy, amino, —NHCH₃, —N(CH₃)₂, —CF₃ or —OCF₃. In anotheraspect, R^(d) is methyl, ethyl, cyclopropyl, cyclobutyl or phenyloptionally substituted with methyl, ethyl, methoxy, ethoxy, F, Cl,cyano, hydroxy, amino, —NHCH₃, —N(CH₃)₂, —CHF₂, —CF₃ or —OCF₃. Inanother aspect, R^(d) is methyl, ethyl or phenyl optionally substitutedwith methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, amino,—NHCH₃, —N(CH₃)₂, —CHF₂, —CF₃ or —OCF₃.

In another aspect of the invention, R⁰ and R¹ are each independently H,methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl or t-butyl; or R¹ isbenzyl, —CH₂pyridine, —CH₂pyrimidine, —CH₂pyridazine, —CH₂pyrazine,—CH₂pyrrole, —CH₂furan, —CH₂thiophene, —CH₂pyrazole, —CH₂imidazole,—CH₂-triazole, —CH₂tetrazole, —CH₂oxazole, —CH₂isoxazole, —CH₂thiazole,—CH₂isothiazole or —CH₂oxadiazole, each optionally substituted with atleast one R⁹ substituent selected from methyl, ethyl, propyl, methoxy,ethoxy, F, Cl, oxo, hydroxy, cyano, —NR^(a)R^(b), —CF₃ and —OCF₃. Inanother aspect, R⁰ and R¹ are each independently H, methyl, ethyl,propyl or isopropyl; or R¹ is benzyl, —CH₂pyridine, —CH₂pyrimidine,—CH₂pyrazole, —CH₂imidazole, —CH₂-triazole, —CH₂tetrazole, —CH₂oxazole,—CH₂isoxazole, —CH₂thiazole, —CH₂isothiazole or —CH₂oxadiazole, eachoptionally substituted with at least one R⁹ substituent selected frommethyl, ethyl, propyl, methoxy, ethoxy, F, Cl, hydroxy, cyano, —NH₂,—CF₃ and —OCF₃. In another aspect, R⁰ is H, methyl, ethyl or propyl; R¹is methyl, ethyl, propyl, isopropyl; or R¹ is benzyl, —CH₂pyridine,—CH₂pyrimidine, —CH₂pyrazole or —CH₂imidazole, each optionallysubstituted with at least one R⁹ substituent selected from methyl,ethyl, methoxy, ethoxy, F, Cl, hydroxy, —CF₃ and —OCF₃. In anotheraspect, R⁰ is H, methyl, ethyl or propyl; and R¹ is methyl, ethyl,propyl or isopropyl. In another aspect, R⁰ is H or methyl; and R¹ ismethyl, ethyl, propyl or isopropyl. In another aspect, R⁰ is H or methyland R¹ is methyl.

In another aspect of the invention, R² and R³ are each independently H,C₁-C₆alkyl, R^(c)NR^(a)R^(b), C₀-C₃alkylC₃-C₆cycloalkyl,C₀-C₃alkylphenyl, C₀-C₃alkylheterocycle, or C₀-C₃alkylheteroaryl;wherein the heterocycle moiety is pyrrolidinyl, piperadinyl,piperazinyl, tetrahydropyran, morpholinyl or thiomorpholinyl; andwherein the heteroaryl moiety is pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazolyl, tetrazolyl or 6,7-dihydro-5H-cyclopenta[d]pyrimidine; andwherein the cycloalkyl, phenyl, heterocycle and heteroaryl rings areeach optionally substituted with at least one R⁹ substituent selectedfrom the group consisting of C₁-C₃alkyl, C₁-C₃alkoxy, hydroxy, halogen,cyclopropyl, cyclobutyl, cyano, amino, —NHCH₃, —N(CH₃)₂, C₁-C₃haloalkyland C₁-C₃haloalkoxy. In another aspect of the invention, R² and R³ areeach independently H, C₁-C₆alkyl, —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; orC₀-C₂cyclopropyl, C₀-C₂cyclobutyl, C₀-C₂cyclopentyl, C₀-C₂cyclohexyl,C₀-C₂phenyl, C₀-C₂piperadinyl, piperazinyl, morpholinyl,tetrahydropyran, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, t-butyl, hydroxy,methoxy, ethoxy, F, Cl, Br, cyano, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂and —OCF₃. In another aspect of the invention, R² and R³ are eachindependently H, C₁-C₆alkyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; orcyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl, cyclopentyl,C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl, piperadinyl,C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-pyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, t-butyl, hydroxy,methoxy, ethoxy, F, Cl, Br, cyano, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂and —OCF₃. In another aspect, R² and R³ are each independently H,C₁-C₆alkyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl,cyclobutyl, C₁cyclobutyl, cyclopentyl, C₁cyclopentyl, cyclohexyl,C₁cyclohexyl, phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl,C₂piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl,pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl,each of which is optionally substituted with at least one R⁹ substituentselected from the group consisting of methyl, ethyl, propyl, isopropyl,t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino,—N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and —OCF₃. In another aspect, R² and R³are each independently H, C₁-C₆alkyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; orcyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl, cyclopentyl,C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl, piperadinyl,C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyridazinyl or pyrazinyl, each of which is optionally substituted withat least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, F,Cl, Br, cyano, cyclopropyl, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and—OCF₃. In another aspect, R² is H, methyl, ethyl, isopropyl,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃ or phenyl. In another aspect,R² is H, methyl, ethyl, cyclopropyl or phenyl. In another aspect, R² isH, methyl or ethyl. In another aspect, R² is H or methyl. In anotheraspect, R² is H. In another aspect, R² is methyl. In another aspect, R³is H, methyl, ethyl, propyl, isopropyl, t-butyl; —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl or pyridinyl, and wherein each ring isoptionally substituted with at least one R⁹ substituent selected fromthe group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl,cyano, amino, —N(CH₃)₂ and —CF₃.

In another aspect of the invention, R² and R³ are taken together withthe nitrogen atom to which they are attached form Ring A, a 4-8 memberedheterocyclic ring or a 5-membered heteroaryl ring, each optionallycontaining at least one additional heteroatom selected from N, O and S;and wherein each ring is optionally substituted with at least one R¹⁰substituent; and wherein each ring is further optionally fused to Ywhich is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl ortriazolyl. In another aspect, R² and R³ taken together with the nitrogenatom to which they are attached form Ring A, a 4-8 membered heterocyclicor 5-membered heteroaryl ring, each optionally containing at least oneadditional heteroatom selected from N, O and S; and wherein each ring isoptionally substituted with at least one R¹⁰ substituent, and whereineach ring is further optionally fused to Y which is phenyl, pyridinyl orpyrimidyl. In another aspect, R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is azetidinyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, eachoptionally substituted with at least one R¹⁰ substituent selected frommethyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN,—N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and wherein eachring is further optionally fused with Y which is phenyl, pyridinyl orpyrimidyl. In another aspect, R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or thiomorpholinyl, each optionallysubstituted with at least one R¹⁰ substituent selected from methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂,hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and wherein each ring isfurther optionally fused with Y which is phenyl, pyridinyl orpyrimidinyl. In another aspect, R² and R³ taken together with thenitrogen atom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃and oxo; and wherein each ring is further optionally fused with Y whichis phenyl or pyridinyl. In another aspect, R² and R³ taken together withthe nitrogen atom to which they are attached form Ring A which ispyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl, each optionally substituted with atleast one R¹⁰ substituent selected from methyl, ethyl, F, Cl, oxo, and—CF₃; and wherein each ring is further optionally fused with Y which isphenyl. In another aspect, R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, F, Cl, oxo, and —CF₃; or Ring Ais indolinyl, isoindolinyl, tetrahydroquinolinyl,dihydropyrrolopyrazinyl, tetrahydroisoquinolinyl, dihydrobenzooxazinylor dihydrobenzothiazinyl optionally substituted with at least one oxo.In another aspect, R² and R³ taken together with the nitrogen atom towhich they are attached form Ring A which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, F, Cl, oxo, and —CF₃; or Ring A is indolinyl,isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl ordihydrobenzothiazinyl optionally substituted with at least one oxo. Inanother aspect, R² and R³ taken together with the nitrogen atom to whichthey are attached form Ring A which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, F, Cl, oxo, and —CF₃.

In another aspect of the invention, R⁵ and R⁶ are each independently H;C₁-C₆alkyl or C₁-C₆alkoxy each optionally substituted with at least onehydroxy; cyano, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸,—C(O)R^(c)NR^(a)R^(b), —C(O)OR^(c)R⁸, —C(O)ONR^(a)R^(b),—R^(c)NR^(a)C(O)R⁸, —R^(c)C(O)OH, —R^(c)C(O)NR^(a)R^(b),—R^(c)NR^(a)C(O)H, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸, —S(O)_(p)R⁸NR^(a)R^(b), —R^(c)S(O)_(p)NR^(a)R^(b),—R^(c)NR^(a)S(O)_(p)R⁸; C₀-C₄alkylphenyl, C₀-C₄alkylC₃-C₆cycloalkyl,C₀-C₄alkylheterocycle, C₀-C₄alkylheteroaryl, wherein the heterocycle andheteroaryl rings are each 5-6 membered monocyclic rings and wherein eachheterocycle and heteroaryl ring each contain at least one heteroatomselected from the group consisting of N, O and S; and wherein thephenyl, cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent. In anotheraspect, R⁵ and R⁶ are each independently H; C₁-C₆alkyl or C₁-C₆alkoxy,each optionally substituted with at least one hydroxy; cyano,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸,—C(O)R^(c)NR^(a)R^(b), —C(O)OR^(c)R⁸, —C(O)ONR^(a)R^(b),—R^(c)NR^(a)C(O)R⁸, —R^(c)C(O)OH, —R^(c)C(O)NR^(a)R^(b),—R^(c)NR^(a)C(O)H, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸, —S(O)_(p)R⁸NR^(a)R^(b), —R^(c)S(O)_(p)NR^(a)R^(b),—R^(c)NR^(a)S(O)_(p)R⁸; phenyl, C₁alkylphenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl,C₁-C₂alkylcyclopentyl, C₁-C₂alkylcyclohexyl, tetrahydrofuranyl,tetrahydropyranyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, C₁-C₂alkyltetrahydro-furanyl, C₁-C₂alkyloxazolidinyl,C₁-C₂alkyltetrahydropyranyl, C₁-C₂alkylpyrrolidinyl,C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl, C₁-C₂morpholinyl;pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkyltriazolyl, C₁-C₂alkyltetrazolyl,C₁-C₂alkyloxazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyridazinyl,C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl; and wherein the phenyl,cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent. In anotheraspect, R⁵ and R⁶ are each independently H; C₁-C₆alkyl or C₁-C₆alkoxyeach optionally substituted with at least one hydroxy; cyano,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸,—C(O)R^(c)NR^(a)R^(b), —C(O)ONR^(a)R^(b), —R^(c)NR^(a)C(O)R⁸,—R^(c)C(O)NR^(a)R^(b), —R^(c)NR^(a)C(O)H, —R^(c)S(O)_(p)R⁸,—R^(c)NR^(a)R^(b), S(O)_(p)R⁸, —S(O)_(p)R⁸NR^(a)R^(b),—R^(c)S(O)_(p)NR^(a)R^(b); phenyl, C₁alkylphenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl,C₁-C₂alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,C₁-C₂alkyloxazolidinyl, C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl,C₁-C₂alkylpiperazinyl, C₁-C₂morpholinyl, C₁-C₂tetrahydrofuran,C₁-C₂tetrahydropyran, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl,C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl; andwherein the phenyl, cycloalkyl ring, heterocycle ring and heteroarylring are each optionally substituted with at least one R¹⁰ substituenteach independently selected from methyl, ethyl, propyl, methoxy, ethoxy,—CHF₂, —CF₃, —OCF₃, F, Cl, amino, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, nitro,cyano, —C(O)CH₃, —NHCH₂C(O)CH₃, —NHCH₂CH₂C(O)CH₃, —C(O)NHCH₃, hydroxyand phenyl. In another aspect, R⁵ and R⁶ are each independently H;C₁-C₆alkyl or C₁-C₆alkoxy each optionally substituted with at least onehydroxy; C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸,—C(O)R^(c)NR^(a)R^(b), —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b),—R^(c)OR^(a), —S(O)_(p)R⁸; phenyl, C₁alkylphenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl,C₁-C₂alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,C₁-C₂alkyloxazolidinyl, C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl,C₁-C₂alkylpiperazinyl, C₁-C₂morpholinyl, C₁-C₂morpholinyl,C₁-C₂piperadinyl, C₁-C₂tetrahydropyranyl, C₁-C₂tetrahydrofuranyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl,C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl; and wherein the phenyl,cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent eachindependently selected from methyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃,—OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy. In anotheraspect, R⁵ and R⁶ are each independently H; C₁-C₆alkyl or C₁-C₆alkoxyeach optionally substituted with at least one hydroxy; C₁-C₆haloalkyl,—OCF₃, —C(O)NR^(a)R⁸, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸; phenyl, C₁alkylphenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl,oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, tetrahydrofuranyl, C₁-C₂alkyloxazolidinyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, C₁-C₂tetrahydrofuranyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl,C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl; and wherein the phenyl,cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent eachindependently selected from methyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃,—OCF₃, F, Cl, amino, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy. Inanother aspect, R⁵ is H, C₁-C₆alkyl, morpholinyl, piperadinyl,—CH₂morpholinyl, —CH₂piperadinyl, —(CH₂)₂morpholinyl or(CH₂)₂piperadinyl. In another aspect, R⁵ is H, methyl, ethyl, propyl,isopropyl, —CH₂morpholinyl, —CH₂piperadinyl, —(CH₂)₂morpholinyl or(CH₂)₂piperadinyl. In another aspect, R⁵ is H, methyl, ethyl, propyl orisopropyl. In another aspect, R⁶ is H; C₁-C₆alkyl or C₁-C₆alkoxy eachoptionally substituted with at least one hydroxy; C₁-C₆haloalkyl, —OCF₃,—C(O)NR^(a)R⁸, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸; phenyl, C₁alkylphenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl,oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, tetrahydrofuranyl, C₁-C₂alkyloxazolidinyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, C₁-C₂tetrahydrofuranyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl,C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl; and wherein the phenyl,cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent eachindependently selected from methyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃,—OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy. In anotheraspect, R⁶ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, methoxy, ethoxy, —CH₂CF₃, —CF₃, —OCF₃; —C(O)NR^(a)R⁸ whereinR^(a) is H or methyl and R⁸ is H, methyl, cyclopropyl, phenyl optionallysubstituted with F, Cl or —CF₃; —(CH₂)S(O)₂R⁸ wherein R⁸ is methyl orphenyl; —CH₂NR^(a)R^(b) or —(CH₂)₂NR^(a)R^(b) wherein R^(a) and R^(b)are each independently H or methyl; —(CH₂)₂OCH₃, —(CH₂)₃OCH₃; phenyl,C₁alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl orC₁-C₂alkylpyrazinyl; and wherein the phenyl, cycloalkyl ring,heterocycle ring and heteroaryl ring are each optionally substitutedwith at least one R¹⁰ substituent each independently selected frommethyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl, amino,—NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy.

In another aspect of the invention, R⁵ and R⁶ taken together with thenitrogen atom to which they are attached form Ring B, a 4-8 memberedheterocyclic or a 5-membered heteroaryl ring, each optionally containingat least one additional heteroatom selected from N, O and S; and whereineach ring is optionally substituted with at least one R⁹ substituent;and wherein each ring is further optionally fused with Y which isphenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl ortriazolyl. In another aspect, R⁵ and R⁶ taken together with the nitrogenatom to which they are attached form Ring B, a 4-8 membered heterocyclicring or a 5-membered heteroaryl ring, each optionally containing atleast one additional heteroatom selected from N, O and S; and whereineach ring is optionally substituted with at least one R⁹ substituent;and wherein each ring is further optionally fused with Y which isphenyl, pyridinyl or pyrimidyl. In another aspect, R⁵ and R⁶ takentogether with the nitrogen atom to which they are attached form Ring Bwhich is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl, each of which is optionally substituted with at leastone R⁹ substituent selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃,—OCHF₂, —OCF₃ and oxo; and wherein each ring is further optionally fusedwith Y which is phenyl or pyridinyl. In another aspect, R⁵ and R⁶ takentogether with the nitrogen atom to which they are attached form Ring Bwhich is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each of which is optionally substituted with at least one R⁹ substituentselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F,Cl, Br, CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; andwherein each ring is further optionally fused with Y which is phenyl. Inanother aspect, R⁵ and R⁶ taken together with the nitrogen atom to whichthey are attached form Ring B which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each of which is optionally substituted with at least one R⁹ substituentselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F,Cl, Br, CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; andwherein each ring is further optionally fused with Y which is phenyl. Inanother aspect, R⁵ and R⁶ taken together with the nitrogen atom to whichthey are attached form Ring B which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each of which is optionally substituted with at least one R⁹ substituentselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F,Cl, Br, CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; orRing B is indolinyl, isoindolinyl, tetrahydroquinolinyl,dihydropyrrolopyrazinyl or tetrahydroisoquinolinyl, dihydrobenzooxazinylor dihydrobenzothiazinyl optionally substituted with at least one oxo.In another aspect, R⁵ and R⁶ taken together with the nitrogen atom towhich they are attached form Ring B which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each of which is optionally substituted with at least one R⁹ substituentselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F,Cl, Br, CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo.

In another aspect of the invention, R⁷ is H, C₁-C₆alkyl, —(CH₂)_(m)NH₂,—(CH₂)_(m)NHCH₃, —(CH₂)_(m)N(CH₃)₂, —(CH₂)_(m)C(O)H, —(CH₂)_(m)C(O)CH₃,—(CH₂)_(m)S(O)_(p)CH₃, —(CH₂)_(m)NHC(O)CH₃, —(CH₂)_(m)NHC(O)NHCH₃,—(CH₂)_(m)NHC(O)N(CH₃)₂ or —(CH₂)_(m)NHC(O)CH₃; wherein m is the integer1, 2, or 3. In another aspect, R⁷ is H, C₁-C₆alkyl, —(CH₂)_(m)NH₂,—(CH₂)_(m)NHCH₃, —(CH₂)_(m)N(CH₃)₂, —(CH₂)_(m)C(O)CH₃,—(CH₂)_(m)S(O)_(p)CH₃ or —(CH₂)_(m)NHC(O)CH₃; wherein m is the integer 1or 2. In another aspect of the invention, R⁷ is H, C₁-C₆alkyl,—(CH₂)NH₂, —(CH₂)NHCH₃, —(CH₂)N(CH₃)₂, —(CH₂)C(O)CH₃, —(CH₂)S(O)_(p)CH₃or —(CH₂)NHC(O)CH₃. In another aspect, R⁷ is H, methyl, ethyl, propyl,isopropyl, t-butyl, —(CH₂)_(m)NH₂, —(CH₂)NHCH₃, —(CH₂)N(CH₃)₂,—(CH₂)C(O)CH₃, —(CH₂)S(O)_(p)CH₃ or —(CH₂)NHC(O)CH₃. In another aspect,R⁷ is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂NH₂, —CH₂NHCH₃or —CH₂N(CH₃)₂. In another aspect, R⁷ is H, methyl, ethyl, propyl,isopropyl or —CH₂N(CH₃)₂. In another aspect, R⁷ is H, methyl, ethyl orpropyl.

In another aspect of the invention, R⁸ is C₁-C₆alkyl, C₁-C₆haloalkyl,—NR^(a)R^(b); or C₀-C₄alkylC₃-C₆cycloalkyl, phenyl, pyrrolyl, pyrazolyl,pyridinyl or pyrimidinyl each optionally substituted with at least onesubstituent selected from C₁-C₆alkyl, C₁-C₆haloalkyl, —NH₂, —NHCH₃,—N(CH₃)₂, halogen, C₁-C₄alkoxy, C₁-C₄haloalkyl and C₁-C₄haloalkoxy. Inanother aspect, R⁸ is methyl, ethyl, propyl; or cyclopropyl,C₁alkylcyclopropyl, phenyl or pyridinyl each optionally substituted withat least one substituent selected from C₁-C₄alkyl, halogen, C₁-C₄alkoxy,—CF₃ and —OCF₃. In another aspect, R⁸ is methyl, ethyl; or cyclopropylor phenyl each optionally substituted with at least one substituentselected from C₁-C₄alkyl, halogen, C₁-C₄alkoxy, —CF₃ and —OCF₃.

In another aspect of the invention, each R⁹ is independently selectedfrom the group consisting of C₁-C₆alkyl, C₁-C₆alkoxy, halogen, oxo,hydroxy, nitro, cyano, —NR^(a)R^(b), C₁-C₆haloalkyl, C₁-C₆haloalkoxy,—S(O)_(p)R⁸, phenyl, tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, piperazinyl, pyrrolyl, furanyl thiophenyl, pyrazolyl,imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl. In yet another aspect, each R⁹ is independently selected fromthe group consisting of C₁-C₆alkyl, C₁-C₆alkoxy, halogen, oxo, hydroxy,nitro, cyano, —NR^(a)R^(b), C₁-C₆haloalkyl, C₁-C₆haloalkoxy,—S(O)_(p)R⁸, phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, morpholinyl, piperazinyl, pyrrolyl, furanyl, thiophenylpyrazolyl, imidazolyl, isoxazolyl, pyridinyl, pyrimidinyl, andpyrazinyl. In yet another aspect, each R⁹ is independently selected fromthe group consisting of C₁-C₆alkyl, C₁-C₆alkoxy, halogen, oxo, hydroxy,nitro, cyano, —NR^(a)R^(b), C₁-C₆haloalkyl, C₁-C₆haloalkoxy,—S(O)_(p)R⁸, phenyl, piperidinyl, morpholinyl, piperazinyl andpyridinyl. In yet another aspect, R⁹ is independently selected from thegroup consisting of C₁-C₆alkyl, C₁-C₆alkoxy, halogen, oxo, hydroxy,cyano, —NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —CHF₂, —CF₃, —OCHF₂, —OCF₃,—S(O)₂CH₃, phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl.In yet another aspect, R⁹ is independently selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,isopropoxy, F, Cl, Br, oxo, hydroxy, cyano, —NHCH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —CHF₂, —CF₃, —OCHF₂, —OCF₃, —S(O)₂CH₃, phenyl, piperidinyl,morpholinyl, piperazinyl and pyridinyl. In yet another aspect, R⁹ isindependently selected from the group consisting of methyl, ethyl,methoxy, ethoxy, isopropoxy, F, Cl, Br, oxo, hydroxy, nitro, cyano,—NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —CHF₂, —CF₃, —OCHF₂, —OCF₃, —S(O)₂CH₃,phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In yetanother aspect, each R⁹ is independently selected from the groupconsisting of methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo,hydroxy, nitro, cyano, —NR^(a)R^(b), —CF₃ and —OCF₃. In yet anotheraspect, each R⁹ is independently selected from the group consisting ofmethyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo, hydroxy, nitro,cyano, —NH₂, —NHCH₃, —N(CH₃)₂, CF₃ and —OCF₃. In another aspect, atleast one R⁹ substituent refers to the integer (n) which is 1, 2 or 3.

In another aspect of the invention, each R¹⁰ is independently selectedfrom C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, halogen,—NR^(a)R^(b), —S(O)_(p)R⁸, nitro, oxo, cyano, —C(O)R^(a), —C(O)OR^(a),—OC(O)OR^(a), —NR^(c)C(O)R^(a), —C(O)NR^(a)R^(b), hydroxy, a 5-6membered heterocyclic ring, a 5-6 membered heteroaryl ring, wherein eachheterocyclic and heteroaryl ring each contain at least one heteroatomselected from the group consisting of N, O and S; and phenyl; andwherein the phenyl, heterocyclic and heteroaryl ring are each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of C₁-C₆alkyl, C₁-C₆alkoxy, halogen, oxo, hydroxy, cyano,—NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —CHF₂, —CF₃, —OCHF₂, —OCF₃, —S(O)₂CH₃,phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In anotheraspect, each R¹⁰ is independently selected from C₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, halogen, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃,nitro, oxo, cyano, —C(O)CH₃, —C(O)OCH₃, —NHCH₂C(O)CH₃, —NHCH₂CH₂C(O)CH₃,—C(O)NHCH₃ and hydroxy; phenyl, tetrahydrofuranyl, pyrrolidinyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl,furanyl, pyrazolyl, imidazolyl, pyridinyl and pyrazinyl, each optionallyand independently substituted with at least one R⁹ substituent selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, methoxy,ethoxy, halogen, oxo, hydroxy, cyano, —NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—CHF₂, —CF₃, —OCHF₂, —OCF₃ and —S(O)₂CH₃. In another aspect, each R¹⁰ isindependently selected from methyl, ethyl, propyl, methoxy, ethoxy,—CHF₂, —CF₃, —OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, nitro, cyano,—C(O)CH₃, —NHC(O)CH₃, —NHCH₂CH₂C(O)CH₃, —C(O)NHCH₃ and hydroxy; phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and pyridinyl, eachoptionally and independently substituted with at least one R⁹substituent selected from the group consisting of methyl, ethyl, propyl,isopropyl, methoxy, ethoxy, halogen, oxo, hydroxy, cyano, —NHCH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and —S(O)₂CH₃. Inanother aspect, each R¹⁰ is independently selected from methyl, ethyl,propyl, methoxy, ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂,—S(O)₂CH₃, nitro, cyano, —C(O)CH₃, —NHCH₂C(O)CH₃, —NHCH₂CH₂C(O)CH₃,—C(O)NHCH₃ and hydroxy. In another aspect, at least one R¹⁰ substituentrefers to the integer (n) which is 1, 2 or 3.

In another aspect, R is H, —C(O)NR^(a)R^(d) or —C(O)OR⁸. In anotheraspect, R is H, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, —C(O)NHCH₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)NHC(CH₃)₃ or —C(O)NHphenyl, wherein the phenyl isoptionally substituted with at least one substituent independentlyselected from F, Cl, —CF₃, cyano, methoxy, ethoxy and —OCF₃. In anotheraspect, R is H, —C(O)NHCH₃, —C(O)N(CH₃)₂ or —C(O)NHphenyl, wherein thephenyl is optionally substituted with at least one substituentindependently selected from F, Cl, —CF₃, cyano, methoxy, ethoxy and—OCF₃. In another aspect, R is H or —C(O)NHphenyl, wherein the phenyl isoptionally substituted with at least one substituent independentlyselected from F, Cl, —CF₃, cyano, methoxy, ethoxy and —OCF₃. In anotheraspect, R is H or —C(O)NHphenyl. In another aspect, R is H.

In yet another aspect, Y is phenyl, pyridinyl, pyrimidyl, pyrazolyl,thienyl, thiazolyl, triazolyl, isothiazolyl or pyrrolyl. In yet anotheraspect, Y is phenyl, pyridinyl, pyrimidyl or pyrazolyl. In yet anotheraspect, Y is phenyl, pyridinyl or pyrimidyl. In yet another aspect, Y isphenyl or pyridinyl. In another aspect, Y is phenyl. In yet anotheraspect, Y is pyridinyl. In yet another aspect, when optionallysubstituted Ring A or Ring B is fused with Y, Ring A or Ring B isoptionally substituted indolinyl, isoindolinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine.

In another aspect, X′ is F, Cl or Br. In another aspect, X′ is F or Cl.In another aspect, X′ is F. In another aspect, X′ is Cl.

In another aspect of the invention, X is R^(a), —(CH₂)_(m)NR⁵R⁶,—(CH₂)_(m)OR⁷, —(CH₂)_(m)SR⁷, —(CH₂)_(m)N₃, —(CH₂)_(m)CN or—(CH₂)_(m)X′; wherein m is the integer 1 or 2. In another aspect, X isR^(a). In another aspect, X is —CH₂NR⁵R⁶. In another aspect, X is—CH₂OR⁷. In another aspect, X is —CH₂SR⁷. In another aspect, X is—CH₂N₃. In another aspect, X is —CH₂CN. In another aspect, X is —CH₂X′.

In another aspect of the invention, p is the integer 0. In anotheraspect, p is the integer 1. In another aspect, p is the integer 2. Inanother aspect of the invention, n is the integer 0, 1 or 2. In yetanother aspect, n is the integer 0 or 1. In yet another aspect, n is theinteger 0. In yet another aspect, n is the integer 1. In yet anotheraspect, n is the integer 2. In yet another aspect, n is the integer 3.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A) that is a Formula (1A) compound wherein R⁰,R¹, R², R³ and X

are as defined herein, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof.

In another aspect of the invention, Formula (A) is selected from thegroup consisting of: Formula (A0), Formula (A1), Formula (A2), Formula(A3), Formula (A4), Formula (A5) or Formula (A6)

stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, Formula (A) compound is Formula (A0). In another aspect,Formula (A) is Formula (A1). In another aspect, Formula (A) is Formula(A2). In another aspect, Formula (A) is Formula (A3) compound. Inanother aspect, Formula (A) is Formula (A4). In another aspect, Formula(A) is Formula (A5). In another aspect, Formula (A) is Formula (A6). Inanother aspect, the preferred Formula (A) is Formula (A1).

In another aspect of the invention, is a Formula (1) compound wherein Rand W are both H; that is a des-cladinose Formula (1.1) compound;

and wherein R⁰, R¹, R² and R³ are as defined herein; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1.1) compound wherein R⁰ is H, methyl, ethyl orpropyl; and R¹, R² and R³ are as defined herein, stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is aFormula (1.1) compound wherein R⁰ is H or methyl; and R¹, R² and R³ areas defined herein, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a Formula (1.1) compoundwherein R⁰ is H or methyl; R¹ is methyl; and R² and R³ are as definedherein, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1.1) compound wherein R⁰ is Hor methyl; R¹ is methyl; and R² and R³ are each independently H,C₁-C₆alkyl, —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or C₀-C₂cyclopropyl,C₀-C₂cyclobutyl, C₀-C₂cyclopentyl, C₀-C₂cyclohexyl, C₀-C₂phenyl,C₀-C₂piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl,pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl orpyrazinyl, each optionally substituted with at least one R⁹ substituentselected from the group consisting of methyl, ethyl, propyl, isopropyl,t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, —N(CH₃)₂,—CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken together with thenitrogen atom to which they are attached form Ring A which isazetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br,CN, —N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and whereineach ring is further optionally substituted with Y which is phenyl,pyridinyl or pyrimidinyl; stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a Formula (1.1) compoundwherein R^(c) is H is methyl; R¹ is methyl; and R² and R³ are eachindependently H, C₁-C₆alkyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; orcyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl, cyclopentyl,C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl, piperadinyl,C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyridazinyl or pyrazinyl, each optionally substituted withat least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, F,Cl, Br, cyano, cyclopropyl, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and—OCF₃; or R² and R³ taken together with the nitrogen atom to which theyare attached form Ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, eachoptionally substituted with at least one R¹⁰ substituent selected frommethyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN,—N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; or Ring A isindolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1.1) compound wherein R⁰is H or methyl; R¹ is methyl; R² is H, methyl, ethyl, isopropyl,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃ or phenyl; and R³ is H, methyl,ethyl, propyl, isopropyl, t-butyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; orcyclopropyl, cyclobutyl, phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl,C₂piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl,or pyridinyl, each optionally substituted with at least one R⁹substituent selected from the group consisting of methyl, ethyl,hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, —N(CH₃)₂ and —CF₃; or R²and R³ taken together with the nitrogen atom to which they are attachedform Ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R¹⁰ substituent selected from methyl, ethyl, F, Cl,oxo and —CF₃; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1.1) Table A compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1.1) compoundstereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a composition comprising a Formula (1.1) Table Acompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, the composition further comprises apharmaceutically acceptable carrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1.1) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1.1) Table A compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect of the method, the inflammatory response is due to abacterial, viral, or fungal infection, stress, and/or an environmentalfactor. In another aspect of the method, the method of treating orpreventing an inflammatory response in an animal prevents or mitigatesthe progression of a respiratory disease or disorder. In another aspectof the method, the animal is livestock. In another aspect of the method,the respiratory disease or disorder is bovine respiratory disease orswine respiratory disease. In another aspect of the method, the methodof treating or preventing an inflammatory response in an animal downregulates TNF-α and IL-6 in the animal.

In another aspect, is the use of a Formula (1.1) compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof; to prepare amedicament for treating or preventing an inflammatory response in ananimal. In another aspect, is the use of a Formula (1.1) Table Acompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect of the use, theinflammatory response is due to a bacterial, viral, or fungal infection,stress, and/or an environmental factor. In another aspect of the use,the use of the medicament for treating or preventing an inflammatoryresponse in the animal prevents or mitigates the progression of arespiratory disease or disorder. In another aspect of the use, theanimal is livestock. In another aspect of the use, the respiratorydisease or disorder is bovine respiratory disease or swine respiratorydisease. In another aspect of the use, the use of administering themedicament to the animal to treat or prevent an inflammatory response inthe animal down regulates TNF-α and IL-6 in the animal.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A), and Formula (A) is Formula (A0); that is aFormula (1-A0)

compound, and wherein R^(a), R⁰, R¹, R² and R³ are as defined herein;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A0) compound wherein R⁰ is H, methyl,ethyl or propyl; and R^(a), R¹, R² and R³ are as defined herein,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A0) compound wherein R⁰ is H, methyl,ethyl or propyl; R^(a) is H or methyl; and R¹, R² and R³ are as definedherein, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A0) compound wherein R⁰ is Hor methyl; R^(a) is H or methyl; and R¹ is H or methyl; and R² and R³are as defined herein, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a Formula (1-A0)compound wherein R⁰ is H or methyl; R¹ is methyl; and R² and R³ are asdefined herein, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A0) compound whereinR⁰ is H or methyl; R¹ is methyl; and R² and R³ are each independently H,C₁-C₆alkyl, —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or C₀-C₂cyclopropyl,C₀-C₂cyclobutyl, C₀-C₂cyclopentyl, C₀-C₂cyclohexyl, C₀-C₂phenyl,C₀-C₂piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl,pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl orpyrazinyl, each optionally substituted with at least one R⁹ substituentselected from the group consisting of methyl, ethyl, propyl, isopropyl,t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, —N(CH₃)₂,—CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken together with thenitrogen atom to which they are attached form Ring A, a 4-8 memberedheterocyclic or 5-membered heteroaryl ring, each optionally containingat least one additional heteroatom selected from N, O and S; and whereineach ring is optionally substituted with at least one R¹⁰ substituent,and wherein each ring is further optionally fused with Y which isphenyl, pyridinyl or pyrimidyl; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A0) compound wherein R⁰ is H or methyl; R¹ is methyl; and R²and R³ are each independently H, C₁-C₆alkyl; —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl,cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyridazinyl or pyrazinyl, each optionally substituted withat least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, F,Cl, Br, cyano, cyclopropyl, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and—OCF₃; or R² and R³ taken together with the nitrogen atom to which theyare attached form Ring A which is pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl or thiomorpholinyl, each optionally substituted with atleast one R¹⁰ substituent selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl,—CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; or Ring A is indolinyl,isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A0) compound whereinR⁰ is H or methyl; R¹ is methyl; R² is H or methyl; and R³ is H, methyl,ethyl or propyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl,cyclobutyl, phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl,C₂piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolylor pyridinyl, each optionally substituted with at least one R⁹substituent selected from the group consisting of methyl, ethyl,hydroxy, methoxy, ethoxy, F, Cl, cyano, —N(CH₃)₂ and —CF₃; or R² and R³taken together with the nitrogen atom to which they are attached formRing A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R¹⁰ substituent selected from methyl, ethyl, F, Cl,oxo and —CF₃; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A0) Table B compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a non-antibacterial Formula (1-A0) Table B compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1-A0)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a composition comprising a Formula (1-A0)Table B compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a composition comprising anon-antibacterial Formula (1-A0) Table B compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1-A0)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a composition comprising a Formula (1-A0)Table B compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a composition comprising anon-antibacterial Formula (1-A0) Table B compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, the composition further comprises a pharmaceutically acceptablecarrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A0) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A0) Table B compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a non-antibacterial Formula (1-A0)Table B compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect of the method, the inflammatoryresponse is due to a bacterial, viral, or fungal infection, stress,and/or an environmental factor. In another aspect of the method, themethod of treating or preventing an inflammatory response in an animalprevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the method, the animal is livestock. Inanother aspect of the method, the respiratory disease or disorder isbovine respiratory disease or swine respiratory disease. In anotheraspect of the method, the method of treating or preventing aninflammatory response in an animal down regulates TNF-α and IL-6 in theanimal.

In another aspect, is the use of a Formula (1-A0) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect, is the use of a Formula (1-A0) Table Bcompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of anon-antibacterial Formula (1-A0) Table B compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof; to prepare amedicament for treating or preventing an inflammatory response in ananimal. In another aspect of the use, the inflammatory response is dueto a bacterial, viral, or fungal infection, stress, and/or anenvironmental factor. In another aspect of the use, the use of themedicament for treating or preventing an inflammatory response in theanimal prevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the use, the animal is livestock. Inanother aspect of the use, the respiratory disease or disorder is bovinerespiratory disease or swine respiratory disease. In another aspect ofthe use, the use of administering the medicament to the animal to treator prevent an inflammatory response in the animal down regulates TNF-αand IL-6 in the animal.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A), and Formula (A) is Formula (A2); that is aFormula (1-A2)

compound; wherein R⁰, R¹, R², R³ and R⁷ are as defined herein;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A2)

compound; wherein R⁰ is H, methyl, ethyl or propyl; R¹ is H or methyl;and R², R³ and R⁷ are as defined herein; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A2) compound; wherein R⁰ is H or methyl; R¹ is H or methyl;and R² and R³ are each independently H, C₁-C₆alkyl; —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl,cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyridazinyl or pyrazinyl, each optionally substituted with at least oneR⁹ substituent selected from the group consisting of methyl, ethyl,propyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano,cyclopropyl, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² andR³ taken together with the nitrogen atom to which they are attached formRing A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R¹⁰ substituent selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl,—CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; or Ring A is indolinyl,isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; and R⁷ is H, C₁-C₆alkyl, —(CH₂)_(m)NH₂,—(CH₂)_(m)NHCH₃, —(CH₂)_(m)N(CH₃)₂, —(CH₂)_(m)C(O)CH₃,—(CH₂)_(m)S(O)_(p)CH₃ or —(CH₂)_(m)NHC(O)CH₃; wherein m is the integer 1or 2; stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A2) wherein R⁰ is H ormethyl; R¹ is methyl; R² is H, methyl, ethyl, cyclopropyl or phenyl; R³is H, methyl, ethyl, propyl, isopropyl, isobutyl, —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro,cyano, —N(CH₃)₂ and —CF₃; or R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, F, Cl, oxo and —CF₃; and R⁷ isH, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂NH₂, —CH₂NHCH₃ or—CH₂N(CH₃)₂, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A2) Table C compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A), and Formula (A) is Formula (A3); that is aFormula (1-A3) compound,

wherein R⁰, R¹, R², R³ and R⁷ are as defined herein; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1-A3) compound; wherein R⁰ is H, methyl, ethyl orpropyl; and R¹, R², R³ and R⁷ are as defined herein; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1-A3) compound; wherein R⁰ is H, methyl, ethyl orpropyl; R¹ is H or methyl; and R², R³ and R⁷ are as defined herein;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A3) compound; wherein R⁰ is H or methyl;R¹ is H or methyl; and R² and R³ are each independently H, C₁-C₆alkyl;—CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl,C₁cyclobutyl, cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl,phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, C₂piperadinyl,piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, t-butyl, hydroxy,methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, —N(CH₃)₂, —CHF₂,—CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃and oxo; or Ring A is indolinyl, isoindolinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; and R⁷ is H, C₁-C₆alkyl, —(CH₂)_(m)NH₂,—(CH₂)_(m)NHCH₃, —(CH₂)_(m)N(CH₃)₂, —(CH₂)_(m)C(O)CH₃,—(CH₂)_(m)S(O)_(p)CH₃ or —(CH₂)_(m)NHC(O)CH₃; wherein m is the integer 1or 2; stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A3) wherein R⁰ is H ormethyl; R¹ is methyl; R² is H, methyl, ethyl, cyclopropyl or phenyl; R³is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro,cyano, —N(CH₃)₂ and —CF₃; or R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, F, Cl, oxo and —CF₃; and R⁷ isH, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂NH₂, —CH₂NHCH₃ or—CH₂N(CH₃)₂, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A3) Table D compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a non-antibacterial Formula (1-A3) Table D compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A), and Formula (A) is Formula (A4); that is aFormula (1-A4) compound

wherein R⁰, R¹, R², R³ and X′ are as defined herein; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1-A4) compound; wherein R⁰ is H, methyl, ethyl orpropyl; and R¹, R², R³ and X′ are as defined herein; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1-A4) compound; wherein R⁰ is H, methyl, ethyl orpropyl; R¹ is H or methyl; and R², R³ and X′ are as defined herein;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A4) compound; wherein R⁰ is H or methyl;R¹ is H or methyl; and R² and R³ are each independently H, C₁-C₆alkyl;—CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl,C₁cyclobutyl, cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl,phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, C₂piperadinyl,piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, t-butyl, hydroxy,methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, —N(CH₃)₂, —CHF₂,—CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃and oxo; or Ring A is indolinyl, isoindolinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; and X is F, Cl, or Br; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A4) wherein R⁰ is H or methyl; R¹ is methyl; R² is H, methyl,ethyl, cyclopropyl or phenyl; R³ is H, methyl, ethyl, propyl, isopropyl,t-butyl, —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl,phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, C₂piperadinyl,piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl,each optionally substituted with at least one R⁹ substituent selectedfrom the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F,Cl, nitro, cyano, —N(CH₃)₂ and —CF₃; or R² and R³ taken together withthe nitrogen atom to which they are attached form Ring A which ispyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinylor thiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, F, Cl, oxo and —CF₃; and X is For Cl; stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A4) Table E compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A), and Formula (A) is Formula (A5); that is aFormula (1-A5)

compound; wherein R⁰, R¹, R² and R³ are as defined herein; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1-A5) compound; wherein R⁰ is H, methyl, ethyl orpropyl; and R¹, R² and R³ are as defined herein; stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A5) compound; wherein R⁰ is H, methyl, ethyl or propyl; R¹ isH or methyl; and R² and R³ are as defined herein; stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A5) compound; wherein R⁰ is H or methyl; R¹ is H or methyl;and R² and R³ are each independently H, C₁-C₆alkyl; —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl,cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyridazinyl or pyrazinyl, each optionally substituted with at least oneR⁹ substituent selected from the group consisting of methyl, ethyl,propyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano,cyclopropyl, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² andR³ taken together with the nitrogen atom to which they are attached formRing A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R¹⁰ substituent selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl,—CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; or Ring A is indolinyl,isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A5) wherein R⁰ is H ormethyl; R¹ is methyl; R² is H, methyl, ethyl, cyclopropyl or phenyl; R³is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro,cyano, —N(CH₃)₂ and —CF₃; or R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl orthiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, F, Cl, oxo and —CF₃;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A5) Table F compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a non-antibacterial Formula (1-A5) Table F compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a Formula (1) compound, wherein R is H, W ifFormula (A) and Formula (A) is Formula (A6) that is a Formula (1-A6)compound, wherein R⁰, R¹,

R² and R³ are as defined herein; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A6) compound, wherein R⁰ is H, methyl, ethyl or propyl; andR¹, R² and R³ are as defined herein; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A6) compound; wherein R⁰ is H, methyl, ethyl or propyl; R¹ isH or methyl; and R² and R³ are as defined herein; stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A6) compound; wherein R⁰ is H or methyl; R¹ is H or methyl;and R² and R³ are each independently H, C₁-C₆alkyl; —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl, C₁cyclobutyl,cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyridazinyl or pyrazinyl, each optionally substituted with at least oneR⁹ substituent selected from the group consisting of methyl, ethyl,propyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano,cyclopropyl, amino, —N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² andR³ taken together with the nitrogen atom to which they are attached formRing A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R¹⁰ substituent selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl,—CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; or Ring A is indolinyl,isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A6) wherein R⁰ is H ormethyl; R¹ is methyl; R² is H, methyl, ethyl, cyclopropyl or phenyl; R³is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each optionally substitutedwith at least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro, cyano, —N(CH₃)₂and —CF₃; or R² and R³ taken together with the nitrogen atom to whichthey are attached form Ring A which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, F, Cl, oxo and —CF₃; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A6) Table G compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1-A2)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a composition comprising a Formula (1-A2)Table C compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a composition comprising a Formula(1-A3) compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a composition comprising a Formula(1-A3) Table D compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a composition comprisinga non-antibacterial Formula (1-A3) compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is acomposition comprising a Formula (1-A4) compound, stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is acomposition comprising a Formula (1-A4) Table E compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a composition comprising a Formula (1-A5) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a composition comprising a non-antibacterial Formula(1-A5) Table F compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a composition comprisinga Formula (1-A6) compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, the composition furthercomprises a pharmaceutically acceptable carrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A2) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A2) Table C compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A3) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A3) Table D compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a non-antibacterial Formula (1-A3)Table D compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a method of treating or preventingan inflammatory response in an animal by administering to said animal inneed thereof, a therapeutically effective amount of a Formula (1-A4)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a method of treating or preventing aninflammatory response in an animal by administering to said animal inneed thereof, a therapeutically effective amount of a Formula (1-A4)Table E compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a method of treating or preventingan inflammatory response in an animal by administering to said animal inneed thereof, a therapeutically effective amount of a Formula (1-A5)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a method of treating or preventing aninflammatory response in an animal by administering to said animal inneed thereof, a therapeutically effective amount of a Formula (1-A5)Table F compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a method of treating or preventingan inflammatory response in an animal by administering to said animal inneed thereof, a therapeutically effective amount of a non-antibacterialFormula (1-A5) Table F compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is amethod of treating or preventing an inflammatory response in an animalby administering to said animal in need thereof, a therapeuticallyeffective amount of a Formula (1-A6) compound, stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is amethod of treating or preventing an inflammatory response in an animalby administering to said animal in need thereof, a therapeuticallyeffective amount of a Formula (1-A6) Table G compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect of the method, the inflammatory response is due to a bacterial,viral, or fungal infection, stress, and/or an environmental factor. Inanother aspect of the method, the method of treating or preventing aninflammatory response in an animal prevents or mitigates the progressionof a respiratory disease or disorder. In another aspect of the method,the animal is livestock. In another aspect of the method, therespiratory disease or disorder is bovine respiratory disease or swinerespiratory disease. In another aspect of the method, the method oftreating or preventing an inflammatory response in an animal downregulates TNF-α and IL-6 in the animal.

In another aspect, is the use of a Formula (1-A2) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect, is the use of a Formula (1-A2) Table Ccompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of aFormula (1-A3) compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof; to prepare a medicament for treating orpreventing an inflammatory response in an animal. In another aspect, isthe use of a non-antibacterial Formula (1-A3) Table D compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect, is the use of a Formula (1-A4)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of aFormula (1-A4) Table E compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof; to prepare a medicament fortreating or preventing an inflammatory response in an animal. In anotheraspect, is the use of a Formula (1-A5) compound, stereoisomers thereof,and pharmaceutically acceptable salts thereof; to prepare a medicamentfor treating or preventing an inflammatory response in an animal. Inanother aspect, is the use of a non-antibacterial Formula (1-A5)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of aFormula (1-A6) compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof; to prepare a medicament for treating orpreventing an inflammatory response in an animal. In another aspect, isthe use of a Formula (1-A6) Table G compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof; to prepare a medicament fortreating or preventing an inflammatory response in an animal. In anotheraspect of the use, the inflammatory response is due to a bacterial,viral, or fungal infection, stress, and/or an environmental factor. Inanother aspect of the use, the use of the medicament for treating orpreventing an inflammatory response in the animal prevents or mitigatesthe progression of a respiratory disease or disorder. In another aspectof the use, the animal is livestock. In another aspect of the use, therespiratory disease or disorder is bovine respiratory disease or swinerespiratory disease. In another aspect of the use, the use ofadministering the medicament to the animal to treat or prevent aninflammatory response in the animal down regulates TNF-α and IL-6 in theanimal.

In another aspect of the invention, is a Formula (1) compound wherein Ris H and W is Formula (A), Formula (A) is Formula (A1); that is aFormula (1-A1) compound;

and wherein R⁰, R¹, R², R³, R⁵ and R⁶ are as defined herein;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A1) compound wherein R⁰ is H, methyl,ethyl or propyl; and R¹, R², R³, R⁵ and R⁶ are as defined herein,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A1) compound wherein R⁰ is H, methyl;ethyl or propyl; R¹ is H or methyl; and R², R³, R⁵ and R⁶ are as definedherein, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A1) compound wherein R⁰ andR¹ are each independently H or methyl; R², R³, R⁵ and R⁶ are as definedherein, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A1) compound wherein R⁰ is Hor methyl; R¹ is methyl; and R², R³, R⁵ and R⁶ are as defined herein,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A1) compound wherein R⁰ is H or methyl;R¹ is methyl; R² and R³ are each independently H, C₁-C₆alkyl;—CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl,C₁cyclobutyl, cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl,phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, C₂piperadinyl,piperazinyl, morpholinyl, tetrahydro-pyran, pyrrolyl, pyrazolyl,triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, eachoptionally substituted with at least one R⁹ substituent selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, t-butyl,hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, —N(CH₃)₂, —CHF₂,—CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken together with the nitrogenatom to which they are attached form Ring A which is pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R¹⁰ substituent selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxyl,—CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and wherein each ring is furtheroptionally fused with Y which is phenyl, pyridinyl or pyrimidinyl; R⁵and R⁶ are each independently H; C₁-C₆alkyl or C₁-C₆alkoxy eachoptionally substituted with at least one hydroxy; C₁-C₆haloalkyl,C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸, —C(O)R^(c)NR^(a)R^(b),—R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a), —S(O)_(p)R⁸; orphenyl, C₁alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl, oxazolidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl, C₁-C₂alkyloxazolidinyl, C₁-C₂alkylpyrrolidinyl,C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl, C₁-C₂morpholinyl,C₁-C₂morpholinyl, C₁-C₂piperadinyl, C₁-C₂tetrahydropyranyl,C₁-C₂tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl,C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl, or C₁-C₂alkylpyrazinyl, eachoptionally substituted with at least one R¹⁰ substituent eachindependently selected from methyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃,—OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy; or R⁵ andR⁶ taken together with the nitrogen atom to which they are attached formRing B which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each optionally substituted with at least one R⁹ substituent selectedfrom methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br,CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and whereineach ring is further optionally fused with Y which is phenyl, pyridinylor pyrimidinyl; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A1) compound whereinR⁰ is H or methyl; R¹ is methyl; R² and R³ are each independently H,C₁-C₆alkyl; —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl,cyclobutyl, C₁cyclobutyl, cyclopentyl, C₁cyclopentyl, cyclohexyl,C₁cyclohexyl, phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl,C₂piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, eachoptionally substituted with at least one R⁹ substituent selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, t-butyl,hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino,—N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken togetherwith the nitrogen atom to which they are attached form Ring A which ispyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinylor thiomorpholinyl, each optionally substituted with at least one R¹⁰substituent selected from methyl, ethyl, F, Cl, oxo and —CF₃; andwherein each ring is further optionally fused with Y which is phenyl; R⁵and R⁶ are each independently H; C₁-C₆alkyl or C₁-C₆alkoxy eachoptionally substituted with at least one hydroxy; C₁-C₆haloalkyl, —OCF₃,—C(O)NR^(a)R⁸, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸; or phenyl, C₁alkylphenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl and C₁-C₂alkylcyclobutyl,oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, tetrahydrofuranyl, C₁-C₂alkyloxazolidinyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, C₁-C₂tetrahydrofuranyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl,C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl, each optionallysubstituted with at least one R¹⁰ substituent each independentlyselected from methyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl,amino, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy; or R⁵ and R⁶taken together with the nitrogen atom to which they are attached formRing B which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl, each optionally substitutedwith at least one R⁹ substituent selected from methyl, ethyl, F, Cl,cyano, hydroxy, oxo and —CF₃; and wherein each ring is furtheroptionally fused with Y which is phenyl; stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is aFormula (1-A1) compound wherein R⁰ is H or methyl; R¹ is methyl; R² isH, methyl, ethyl, isopropyl, cyclopropyl, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃ orphenyl; R³ is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each optionally substitutedwith at least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, —N(CH₃)₂and —CF₃; or R² and R³ taken together with the nitrogen atom to whichthey are attached form Ring A which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, F, Cl, oxo and —CF₃; or Ring B is indolinyl,isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; R⁵ is H, C₁-C₆alkyl, morpholinyl, piperadinyl,—CH₂morpholinyl, —CH₂piperadinyl, —(CH₂)₂morpholinyl or(CH₂)₂piperadinyl; R⁶ is H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, methoxy, ethoxy, —CH₂CF₃, —CF₃ or —OCF₃;—C(O)NR^(a)R⁸ wherein R^(a) is H or methyl and R⁸ is H, methyl,cyclopropyl, phenyl optionally substituted with F, Cl or —CF₃;—(CH₂)S(O)₂R⁸ wherein R⁸ is methyl or phenyl; —CH₂NR^(a)R^(b) or—(CH₂)₂NR^(a)R^(b)wherein R^(a) and R^(b) are each independently H ormethyl; —(CH₂)₂OCH₃, —(CH₂)₃OCH₃; or phenyl, C₁alkylphenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl,C₁-C₂alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl andC₁-C₂alkylpyrazinyl; each optionally substituted with at least one R¹⁰substituent each independently selected from methyl, ethyl, methoxy,ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl, amino, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃,cyano and hydroxy; or R⁵ and R⁶ taken together with the nitrogen atom towhich they are attached form Ring B which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each optionally substituted with at least one R⁹ substituent selectedfrom methyl, ethyl, F, Cl, cyano, hydroxy, oxo and —CF₃; or Ring B isindolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl ordihydrobenzothiazinyl optionally substituted with at least one oxo;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A1) compound wherein R⁰ is H or methyl;R¹ is methyl; R² is H or methyl; R³ is methyl, ethyl or propyl,isopropyl, t-butyl, —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl,cyclobutyl, phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, piperazinyl,morpholinyl or pyridinyl, each optionally substituted with at least oneR⁹ substituent selected from the group consisting of methyl, ethyl,hydroxy, methoxy, ethoxy, F, Cl, cyano, —N(CH₃)₂ and —CF₃; R⁵ is H,methyl, ethyl, propyl or isopropyl; R⁶ is H, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, —CH₂CF₃, —CF₃,—OCF₃; —C(O)NR^(a)R⁸ wherein R^(a) is H or methyl and R⁸ is H, methyl,cyclopropyl, phenyl optionally substituted with F, Cl or —CF₃;—(CH₂)S(O)₂R⁸ wherein R⁸ is methyl or phenyl; —CH₂NR^(a)R^(b) or—(CH₂)₂NR^(a)R^(b)wherein R^(a) and R^(b) are each independently H ormethyl; —(CH₂)₂OCH₃, —(CH₂)₃OCH₃; or phenyl, C₁alkylphenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl,C₁-C₂alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl orC₁-C₂alkylpyrazinyl; each optionally substituted with at least one R¹⁰substituent each independently selected from methyl, ethyl, methoxy,ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl, amino, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃,cyano and hydroxy; stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a Formula (1-A1) Table Hcompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a non-antibacterial Formula (1-A1) TableH compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A1) that is1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1-A1)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a composition comprising a Formula (1-A1)Table H compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a composition comprising anon-antibacterial Formula (1-A1) Table H compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a composition comprising a Formula (1-A1) compound that isH-11;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, the composition further comprises a pharmaceuticallyacceptable carrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A1) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A1) Table H compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a non-antibacterial Formula (1-A1)Table H compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a method of treating or preventingan inflammatory response in an animal by administering to said animal inneed thereof, a therapeutically effective amount Example H-11;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect of the method, the inflammatory response is due to abacterial, viral, or fungal infection, stress, and/or an environmentalfactor. In another aspect of the method, the method of treating orpreventing an inflammatory response in an animal prevents or mitigatesthe progression of a respiratory disease or disorder. In another aspectof the method, the animal is livestock. In another aspect of the method,the respiratory disease or disorder is bovine respiratory disease orswine respiratory disease. In another aspect of the method, the methodof treating or preventing an inflammatory response in an animal downregulates TNF-α and IL-6 in the animal.

In another aspect, is the use of a Formula (1-A1) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect, is the use of a Formula (1-A1) Table Hcompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of anon-antibacterial Formula (1-A1) Table H compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof; to prepare amedicament for treating or preventing an inflammatory response in ananimal. In another aspect, is the use of H-11;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect of the use, the inflammatory response isdue to a bacterial, viral, or fungal infection, stress, and/or anenvironmental factor. In another aspect of the use, the use of themedicament for treating or preventing an inflammatory response in theanimal prevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the use, the animal is livestock. Inanother aspect of the use, the respiratory disease or disorder is bovinerespiratory disease or swine respiratory disease. In another aspect ofthe use, the use of administering the medicament to the animal to treator prevent an inflammatory response in the animal down regulates TNF-αand IL-6 in the animal.

In another aspect of the invention, is a Formula (1-A1) compound,wherein R¹ is methyl and R² and R³ taken together with the nitrogen atomto which they are attached form Ring A which is optionally substitutedby at least one R¹⁰ substituent, that is a Formula (1-A1b) compound,wherein R^(c), R⁵, R⁶, Ring A, R¹⁰ and n are as defined

herein, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is Formula (1-A1a) compound wherein R⁰ is Hor methyl; and R⁵, R⁶, R¹⁰, Ring A and n are as defined herein,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is Formula (1-A1a) compound wherein R⁰ is H or methyl;R⁵ is H, methyl, ethyl, propyl, isopropyl, —CH₂morpholinyl,—CH₂piperadinyl, —(CH₂)₂morpholinyl or (CH₂)₂piperadinyl; R⁶ is H;C₁-C₆alkyl or C₁-C₆alkoxy each optionally substituted with at least onehydroxy; C₁-C₆haloalkyl, —OCF₃, —C(O)NR^(a)R⁸, —R^(c)S(O)_(p)R⁸,—R^(c)NR^(a)R^(b), —R^(c)OR^(a) or —S(O)_(p)R⁸; or phenyl,C₁alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl, oxazolidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl, C₁-C₂alkyloxazolidinyl, C₁-C₂alkylpyrrolidinyl,C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl, C₁-C₂morpholinyl,C₁-C₂tetrahydropyranyl, C₁-C₂tetrahydrofuranyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl orC₁-C₂alkylpyrazinyl, each optionally substituted with at least one R¹⁰substituent each independently selected from methyl, ethyl, methoxy,ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyanoand hydroxy; and Ring A is pyrrolyl, pyrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, eachoptionally substituted with at least one R¹⁰ substituent selected frommethyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN,—N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; or Ring A isindolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a Formula (1-A1a) compound whereinR⁰ is H or methyl; R⁵ is H, methyl, ethyl, propyl or isopropyl; R⁶ is H,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy,ethoxy, —CH₂CF₃, —CF₃, —OCF₃; —C(O)NR^(a)R⁸ wherein R^(a) is H or methyland R⁸ is H, methyl, cyclopropyl, phenyl optionally substituted with F,Cl or —CF₃; —(CH₂)S(O)₂R⁸ wherein R⁸ is methyl or phenyl;—CH₂NR^(a)R^(b) or —(CH₂)₂NR^(a)R^(b) wherein R^(a) and R^(b) are eachindependently H or methyl; —(CH₂)₂OCH₃, (CH₂)₃OCH₃; or phenyl,C₁alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl orC₁-C₂alkylpyrazinyl, each optionally substituted with at least one R¹⁰substituent each independently selected from methyl, ethyl, methoxy,ethoxy, —CHF₂, —CF₃, —OCF₃, F, Cl, amino, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃,cyano and hydroxy; and Ring A is pyrrolyl, pyrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, eachoptionally substituted with at least one R¹⁰ substituent selected frommethyl, ethyl, F, Cl, oxo and —CF₃; or Ring A is indolinyl,isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl, ordihydrobenzothiazinyl optionally substituted with at least one oxo; orRing A is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl or thiomorpholinyl, each optionally substituted with atleast one R¹⁰ substituent selected from methyl, ethyl, F, Cl, oxo and—CF₃; stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a Formula (1-A1a) Table I compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a non-antibacterial Formula (1-A1a) Table I compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1-A1a)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a composition comprising a Formula(1-A1a) Table I compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof.

In another aspect, is a composition comprising a non-antibacterialFormula (1-A1a) Table I compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, thecomposition further comprises a pharmaceutically acceptable carrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A1a) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A1a) Table I compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a non-antibacterial Formula (1-A1a)Table I compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect of the method, the inflammatoryresponse is due to a bacterial, viral, or fungal infection, stress,and/or an environmental factor. In another aspect of the method, themethod of treating or preventing an inflammatory response in an animalprevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the method, the animal is livestock. Inanother aspect of the method, the respiratory disease or disorder isbovine respiratory disease or swine respiratory disease. In anotheraspect of the method, the method of treating or preventing aninflammatory response in an animal down regulates TNF-α and IL-6 in theanimal.

In another aspect, is the use of a Formula (1-A1a) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect, is the use of a Formula (1-A1a) Table Icompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of anon-antibacterial Formula (1-A1a) Table I compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof; to prepare amedicament for treating or preventing an inflammatory response in ananimal. In another aspect of the use, the inflammatory response is dueto a bacterial, viral, or fungal infection, stress, and/or anenvironmental factor. In another aspect of the use, the use of themedicament for treating or preventing an inflammatory response in theanimal prevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the use, the animal is livestock. Inanother aspect of the use, the respiratory disease or disorder is bovinerespiratory disease or swine respiratory disease. In another aspect ofthe use, the use of administering the medicament to the animal to treator prevent an inflammatory response in the animal down regulates TNF-αand IL-6 in the animal.

In another aspect of the invention, is a Formula (1-A1) compound whereinR¹ is methyl, and R⁵ and R⁶ taken together with the nitrogen atom towhich they are attached form Ring B that is optionally substituted withat least one R⁹ substituent; that is a Formula (1-A1b) compound; whereinR^(c), R², R³, Ring B, R⁹ and n are as defined herein,

stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a Formula (1-A1b) compound, wherein R⁰ is H ormethyl; and R², R³, Ring B, R⁹ and n are as defined herein. In anotheraspect, is a Formula (1-A1b) compound, wherein R⁰ is H or methyl; R² isH, methyl, ethyl, isopropyl, cyclopropyl, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃ orphenyl; R³ is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, C₂piperadinyl, piperazinyl, morpholinyl,tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each optionally substitutedwith at least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, —N(CH₃)₂and —CF₃; or R² and R³ taken together with the nitrogen atom to whichthey are attached form Ring A which is pyrrolyl, pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, F, Cl, oxo and —CF₃; and wherein each ring isfurther optionally fused with Y which is phenyl; and R⁵ and R⁶ takentogether with the nitrogen atom to which they are attached form Ring Bwhich is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl or thiomorpholinyl, each optionally substituted with atleast one R⁹ substituent selected from methyl, ethyl, hydroxy, F, Cl,cyano, oxo and —CF₃; and wherein each ring is further optionally fusedwith Y which is phenyl; stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a Formula (1-A1b)compound, wherein R⁰ is H or methyl; R² is H or methyl; and R³ ismethyl, ethyl, propyl, isopropyl, t-butyl, —CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂;or cyclopropyl, cyclobutyl, phenyl, C₁phenyl, piperadinyl,C₁-piperadinyl, piperazinyl, morpholinyl or pyridinyl, each optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano,—N(CH₃)₂ and —CF₃; and Ring B is pyrrolyl, pyrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, eachoptionally substituted with at least one R⁹ substituent selected frommethyl, ethyl, F, Cl, hydroxy, cyano, oxo and —CF₃; or Ring A isindolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline,dihydrobenzooxazine or dihydrobenzothiazine optionally substituted withat least one oxo; or Ring B is pyrrolyl, pyrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, eachoptionally substituted with at least one R⁹ substituent selected frommethyl, ethyl, F, Cl, hydroxy, cyano, oxo and —CF₃; stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, is a Formula (1-A1b) Table J compound, stereoisomers thereof,and pharmaceutically acceptable salts thereof. In another aspect, is anon-antibacterial Formula (1-A1b) Table J compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof.

In another aspect, is a composition comprising a Formula (1-A1b)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof. In another aspect, is a composition comprising a Formula(1-A1b) Table J compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. In another aspect, is a composition comprisinga non-antibacterial Formula (1-A1b) Table J compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof. In anotheraspect, the composition further comprises a pharmaceutically acceptablecarrier.

In another aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A1b) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a Formula (1-A1b) Table J compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of a non-antibacterial Formula (1-A1b)Table J compound, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect of the method, the inflammatoryresponse is due to a bacterial, viral, or fungal infection, stress,and/or an environmental factor. In another aspect of the method, themethod of treating or preventing an inflammatory response in an animalprevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the method, the animal is livestock. Inanother aspect of the method, the respiratory disease or disorder isbovine respiratory disease or swine respiratory disease. In anotheraspect of the method, the method of treating or preventing aninflammatory response in an animal down regulates TNF-α and IL-6 in theanimal.

In another aspect, is the use of a Formula (1-A1b) compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof; toprepare a medicament for treating or preventing an inflammatory responsein an animal. In another aspect, is the use of a Formula (1-A1b) Table Jcompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; to prepare a medicament for treating or preventing aninflammatory response in an animal. In another aspect, is the use of anon-antibacterial Formula (1-A1b) Table J compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof; to prepare amedicament for treating or preventing an inflammatory response in ananimal. In another aspect of the use, the inflammatory response is dueto a bacterial, viral, or fungal infection, stress, and/or anenvironmental factor. In another aspect of the use, the use of themedicament for treating or preventing an inflammatory response in theanimal prevents or mitigates the progression of a respiratory disease ordisorder. In another aspect of the use, the animal is livestock. Inanother aspect of the use, the respiratory disease or disorder is bovinerespiratory disease or swine respiratory disease. In another aspect ofthe use, the use of administering the medicament to the animal to treator prevent an inflammatory response in the animal down regulates TNF-αand IL-6 in the animal.

In another aspect of the invention, is a Formula (1) compound, wherein Wis Formula (A), and Formula (A) is Formula (A1), R is —C(O)NHR^(d); R⁰and R² are both H, R¹ is methyl, R⁵ and R⁶ are joined together with theN atom they share to form Ring B which is 4-methylpiperazine, that is acompound selected from:(2S,3R,4S,6R)-4-(3-(tert-butyl)-1-methylureido)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylethylcarbamate;(2S,3R,4S,6R)-4-(3-(tert-butyl)-1-methylureido)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yltert-butylcarbamate;(2S,3R,4S,6R)-4-(3-(4-(dimethylamino)phenyl)-1-methylureido)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(4-(dimethylamino)phenyl)carbamate; and(2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureido)tetrahydro-2H-pyran-3-ylphenylcarbamate. In another aspect of the invention, is a Formula (1)compound, wherein W is Formula (A), and Formula (A) is Formula (A2), R⁰and R² are both H, R¹ is methyl, R³ is phenyl, R⁷ is ethyl, and R is—C(O)NHPhenyl: that is(2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureido)tetrahydro-2H-pyran-3-ylphenylcarbamate, stereoisomers thereof, and pharmaceutically acceptablesalts thereof.

In another aspect of the invention, is a Formula (1) compound, wherein Wis Formula (A), and Formula (A) is Formula (A3), R⁰ and R² are both H,R¹ is methyl, R³ is phenyl, R⁷ is propyl, and R is —C(O)NHPhenyl: thatis(2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureido)tetrahydro-2H-pyran-3-ylphenylcarbamate, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect of the invention, is a Formula (1)compound wherein W is Formula (A), Formula (A) is Formula (A4), R⁰ andR² are both H, R¹ is methyl, R³ is phenyl, X is chloro, and R is—C(O)NHPhenyl: that is2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureido)tetrahydro-2H-pyran-3-ylphenylcarbamate, stereoisomers thereof, and pharmaceutically acceptablesalts thereof.

In another aspect of the invention, is a Formula (1) compound, wherein Wis Formula (A), Formula (A) is Formula (A6), R⁰ and R² are both H, R¹ ismethyl, R³ is phenyl and R is —C(O)NHPhenyl: that is(2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureido)tetrahydro-2H-pyran-3-ylphenylcarbamate, stereoisomers thereof, and pharmaceutically acceptablesalts thereof. In another aspect, is a composition comprising any one ofthe Formula (1) phenylcarbamate compounds, and wherein the compositionfurther comprises a pharmaceutically acceptable carrier. In anotheraspect, is a method of using any one of the Formula (1) phenylcarbamatecompounds for treating or preventing an inflammatory response in ananimal by administering to said animal in need thereof, atherapeutically effective of a Formula (1) phenylcarbamate compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inanother aspect, is the use of any one of the Formula (1)phenylcarbamates for preparing a medicament for treating or preventingan inflammatory response in an animal.

In another aspect of the invention, is the combination of a Formula (1)compound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof; with at least one additional pharmaceutical agent that can bean antibacterial agent, anti-inflammatory agent, vitamin, mineral, ormixture thereof. The compounds of the invention can be co-administeredwith the additional pharmaceutical agent(s) simultaneously, separate, orsequentially for treating a bacterial infection and/or preventing aninflammatory and/or immune response in an animal from cascading to thefull BRD disease complex.

In another aspect of the invention, is a composition comprising M9,stereoisomers thereof, and pharmaceutically acceptable salts thereof. Inyet another aspect, the composition comprising M9 further comprises apharmaceutically acceptable carrier. In yet another aspect of theinvention, is a method of treating or preventing an inflammatoryresponse in an animal by administering to said animal in need thereof, atherapeutically effective amount of M9, stereoisomers thereof, andpharmaceutically acceptable salts thereof. In another aspect, is amethod for treating or preventing an inflammatory response in an animalwherein the inflammatory response is due to a bacterial, viral, orfungal infection, stress, and/or an environmental factor. In anotheraspect, is a method for treating or preventing the inflammatory responsein an animal wherein M9 mitigates the progression of a respiratorydisease or disorder. In yet another aspect, the animal is livestock. Inyet another aspect, the respiratory disease or disorder is bovinerespiratory disease or swine respiratory disease.

In another aspect, is a Formula (1) compound that is a non-antibacterialFormula (1.1) Table A compound selected from the group consisting ofExample A-1, A-2, A-3, A-4, A-6, A-7, A-9 through A-12, A-14 throughA-21 and A-22 through A-26; or a non-antibacterial Formula (1-A0) TableB compound selected from the group consisting of Example B-1a throughB-6 and B-8 through B-15; or a non-antibacterial Formula (1-A2) Table Ccompound selected from the group consisting of Example C-1 and C-3; or anon-antibacterial Formula (1-A3) Table D compound selected from ExampleC-1 or C-2; or a non-antibacterial Formula (1-A4) Table E compoundselected from the group consisting of Example E-1 through E-3; or anon-antibacterial Formula (1-A5) Table F compound that is Example F-1 orF-2; or a non-antibacterial Formula (1-A6) Table G compound selectedfrom the group consisting of Example G-1 through G-3; or anon-antibacterial Formula (1-A1) Table H compound selected from thegroup consisting of Example H-1, H-2, H-4, H-6, H-8 through H-14, H16,H-17, H-21, H-24, H-25, H-27, H-28, H-29, H-31 through H-35, H-37, H-39through H-43, H-47, H-48, H49, H-51 through H-57, H-59, H-60, H-62through H-65, H-77, H-79, H-80, H-82 through H-86, H-88, H-91 throughH-97, and H-99 through H-103; or a non-antibacterial Formula (1-A1a)Table I compound selected from the group consisting of Example I-1 and1-3 through 1-7; or a non-antibacterial Formula (1-A1b) Table J compoundselected from the group consisting of Example J-4, J-10, J-12, J-13,J-15, J-16, J-19 through J-24 and J-27 through J-31; stereoisomersthereof, and pharmaceutically acceptable salts thereof; a compositioncomprising one of these non-antibacterial compounds; a method of usingone of these non-antibacterial compounds to treat or prevent aninflammatory response in an animal; or the use of one of thesenon-antibacterial compounds to prepare a medicament for treating ofpreventing an inflammatory response in an animal.

Discussion

DESCRIPTION OF FIGURES

FIG. 1. Mechanism of an Immunomodulator in Context of BRD Progression

FIG. 2. Clinical and Genomics Temporal Data Summary

FIG. 3. Plasma Cytokine (IL-6, IL-8, IL-10 and IFN-γ) Levels uponArrival to the Feedlot for Calves at Risk for BRD

FIG. 4. Example H-11 Dose Dependent Cytokines-Whole Blood Assay: IL-6(A), TNF-α (B) and IL-1β (C)

FIG. 5. IL-36RA Change (%) During the Natural Infection Bovine Studies

FIG. 6. Biomarker Evaluation for M9 and Draxxin Intratracheal LungChallenge; IL-6 (A) and CD163 Biomarker (B) Results

FIG. 7. Biomarker Evaluation for Example H-91 Intratracheal LungChallenge: IL-6 (A) and CD163 Biomarker (B) Results

FIG. 8. Biomarker Evaluation for Example H-11 Intratracheal LungChallenge: Neutrophils (A), IL-6 (B) and CD163 (C) Results

FIG. 9. Intracellular Flow Cytometric Characterization of CD4+ T HelperCell Subtypes

FIG. 10. IL-17 Levels from the Airway of Animals Challenged with M.haemolytica Administered Example H-11

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents. etc., defined hereinand as such may vary. The terminology used herein is for the purpose ofdescribing embodiments only and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.

Unless otherwise defined, scientific and technical terms used inconnection with the compounds of the invention defined herein shall havethe meanings that are commonly understood by those of ordinary skill inthe art. Further, unless otherwise required by context, singular termsshall include pluralities and plural terms shall include the singular.Generally, nomenclatures utilized in connection with, and techniques of,chemistry synthesis, macrolides, and immunomodulation defined herein arethose that are well known and commonly used in the art.

Definitions

For purposes of the present invention, as described and claimed herein,the following terms and phrases are defined as follows:

“Additional pharmaceutical agent(s)” as used herein, unless otherwiseindicated, refers to other pharmaceutical compounds or products thatprovide a therapeutically effective amount of said agents that areuseful for the treatment of a bacterial infection in an animal and/ormodulating an immune response, as defined herein.

“Alkoxy”, as used herein, unless otherwise indicated, refers to anoxygen moiety having a further alkyl substituent. The alkyl portion(i.e., alkyl moiety) of an alkoxy group has the same definition asbelow. Non-limiting examples include: —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—OC(CH₃)₃, and the like.

“Alkyl”, as used herein, unless otherwise indicated, refers to saturatedmonovalent hydrocarbon alkane radicals of the general formulaC_(n)H_(2n+1). The alkane radical may be straight or branched and may beunsubstituted or substituted. For example, the term “(C₁-C₆)alkyl”refers to a monovalent, straight or branched aliphatic group containing1 to 6 carbon atoms; similarly, C₁-C₃ alkyl refers to a monovalent,straight or branched aliphatic group containing 1 to 3 carbon atoms,etc. Non-exclusive examples of (C₁-C₆) alkyl groups include, but are notlimited to methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl,n-propyl, n-butyl, i-butyl, s-butyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl,2-methylpentyl, hexyl, and the like. The alkyl moiety may be attached tothe chemical moiety by any one of the carbon atoms of the aliphaticchain. Alkyl groups are optionally substituted as defined herein.Further when used in compound words such as alkylphenyl, said alkylmoiety has the same meaning as herein defined and may be attached to thechemical moiety by any one of the carbon atoms of the aliphatic chain.Non-limiting examples of the compound word, C₀-C₄alkylphenyl include:C₀phenyl (phenyl), C₁alkylphenyl (—CH₂phenyl), C₂alkylphenyl(—CH₂CH₂phenyl), and the like.

“Animal(s)”, as used herein, unless otherwise indicated, refers to anindividual animal that is a mammal. Specifically, mammal refers to avertebrate animal that is human and non-human, which are members of thetaxonomic class Mammalia. Non-exclusive examples of non-human mammalsinclude companion animals and livestock. Non-exclusive examples of acompanion animal include: dog, cat and horse. Non-exclusive examples oflivestock include: swine, camel, rabbits, goat, sheep, deer, elk, bovine(cattle and μ.

“Antibacterial”, as used herein, unless otherwise indicated, refers to acompound with a minimum inhibitory concentration (MIC)≤64 μg/mL for theBRD pathogens, M. haemolytica and P. multocida. The term“non-antibacterial” as used herein, unless otherwise indicated, refersto a compound with an MIC≥64 μg/mL for the BRD pathogens, M. haemolyticaand P. multocida.

“Aryl”, as used herein, unless otherwise indicated, refers to anunsaturated, aromatic monocyclic ring of 6 carbon members or to anunsaturated, aromatic polycyclic ring of from 10 to 14 carbon members.Examples of such aryl rings include, and are not limited to, phenyl,naphthalenyl or anthracenyl. Further when used in compound words such asalkylaryl (e.g., alkylphenyl), said alkyl and aryl moiety have the samemeaning as herein defined and may be attached to the chemical moiety byany one of the carbon atoms of the aliphatic chain or ring carbon.Examples of C₀-C₃alkylphenyl, for example: C₀alkylphenyl is phenyl;C₁-alkylphenyl is —CH₂phenyl (benzyl); and C₂-alkylphenyl is—CH₂CH₂phenyl. The phenyl ring is optionally substituted as definedherein.

“Azalide” as used herein, unless otherwise indicated, refers to a classof macrolides which contain a nitrogen atom in the macrolide ring whichimparts different pharmacokinetic properties and is associated withgreater stability of the molecule.

“Chiral”, as used herein, unless otherwise indicated, refers to thestructural characteristic of a molecule that makes it impossible tosuperimpose it on its mirror image, (e.g., “R” and “S” enantiomers).

“Composition”, as used herein, unless otherwise indicated, refers to acompound of the invention that is formulated with at least onepharmaceutically acceptable excipient for dosing administration.

“Compounds of the present invention”, “compounds of the invention”, asused herein, unless otherwise indicated, includes a Formula (1), (1A),(1.1), (1-A0), (1-A1), (1-A1a), (1-A1b), (1-A2), (1-A3), (1-A4), (1-A5)and (1-A6) compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof. The term(s) also include the respective13-membered macrolides that are in equilibrium with the 15-memberedmacrolide ring of the stated Formula's; and includes the class ofazalides.

“Cycloalkyl”, as used herein, unless otherwise indicated, includes fullysaturated or partially saturated carbocyclic alkyl moieties, i.e., a 3-to 6-membered ring containing only carbon atoms and can be monocyclic orpart of a fused ring or bridged ring moiety. Examples of saturatedcarbocyclic (cycloalkyl) rings include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Non-limitingexamples of partially saturated cycloalkyls include: cyclopropene,cyclobutene, and the like. Preferred cycloalkyls are 3- to 6-memberedsaturated monocyclic rings including cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. The cycloalkyl group may be attached to thechemical moiety by any one of the carbon atoms within the carbocyclicring. Cycloalkyl groups are optionally substituted with at least onesubstituent. Further when used in compound words such asalkylcycloalkyl, said alkyl and cycloalkyl moiety have the same meaningas herein defined and may be attached to the chemical moiety by any oneof the carbon atoms of the aliphatic chain. Examples ofC₀-C₄alkylC₃-C₆cycloalkyl include, for example: C₀alkylC₃-C₆cycloalkylis C₃-C₆cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl); C₁-alkylC₃-C₆cycloalkyl is —CH₂C₃-C₆cycloalkyl (e.g.,—CH₂-cyclopropyl, —CH₂-cyclohexyl, and the like);C₂-alkylC₃-C₆cycloalkyl is —CH₂CH₂C₃-C₆cycloalkyl (e.g.,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclopentyl) and the like. Cycloalkylmoieties are optionally substituted as defined herein.

“Cytokine”, as used herein, unless otherwise indicated, refers togeneral class of biological molecules which effect/affect all types ofcells and influence immunological responses and non-immunologicalbiologic processes. The definition is meant to include, but is notlimited to, those biological molecules that act locally or systemically,and which, when used in the compositions or methods of the presentinvention serve to regulate or modulate an animal's immune response.Exemplary cytokines for use in practicing the invention include but arenot limited to interleukins (e.g. among IL-1 to IL-29, in particular,IL-1, IL-1β, IL-6, IL-9, IL-10 and IL-12), chemokines (e.g. CCL2-5,CCL10, CCL11, CXCL8 (IL-8) and CXCL10), tumor necrosis factors (e.g.,TNF-α and TNF-β), and in particular, NFJ-B, which mediates the inductionof pro-inflammatory cytokines, such as TNF-α, IL-1 and IL-6, inmonocytes and macrophages.

“Halogen” or “halo”, as used herein, unless otherwise indicated, refersto fluorine, chlorine, bromine and iodine. Further, when used incompound words such as “haloalkyl” or “haloalkoxy”, said alkyl andalkoxy may be partially or fully substituted with halogen atoms whichmay be the same or different and said alkyl and alkoxy moiety has thesame meaning as above and may be attached to the chemical moiety by anyone of the carbon atoms of the aliphatic chain. Examples of “haloalkyl”include F₃C—, ClCH₂—, CF₃CH₂— and CF₃CCl₂—, and the like. The term“haloalkoxy” is defined analogously to the term “haloalkyl”. Examples of“haloalkoxy” include CF₃O—, CCl₃CH₂O—, HCF₂CH₂CH₂O— and CF₃CH₂O—, andthe like.

“Heteroaryl” or “Het”, as used herein, unless otherwise indicated,refers to a 5- to 6-membered aromatic monocyclic ring or an 8- to10-membered fused aromatic ring where said monocyclic- and fused-ringmoiety contains one or more heteroatoms each independently selected fromN, O and S, preferably from one to four heteroatoms. Non-exclusiveexamples of monocyclic heteroaryls include pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, and the like. Non-exclusive examples of fusedheteroaryls include: benzofuranyl, benzothiophenyl, indolyl,benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine,thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole, and the like. Theheteroaryl group may be attached to the chemical moiety by any one ofthe carbon atoms or nitrogen heteroatoms within the monocyclic or fusedring. Further when used in compound words such as alkylheteroaryl (e.g.,C₀-C₄alkylheteroaryl), said alkyl and heteroaryl moiety have the samemeaning as herein defined and may be attached to the chemical moiety byany one of the carbon atoms of the aliphatic chain. For example,C₀alkylheterocycle is heterocycle (e.g., pyrazolyl, imidazolyl,pyridinyl, piperazinyl, and the like), C₁alkylheteroaryl is—CH₂heteroaryl (e.g., —CH₂imidazolyl, —CH₂pyridinyl, and the like),C₂alkylheteroaryl is —CH₂CH₂heteroaryl (e.g., —CH₂CH₂ pyrazolyl,—CH₂CH₂oxazolyl, —CH₂CH₂pyrimidinyl, and the like), and the like.Heteroaryls are optionally substituted as defined herein.“Heterocycle”, as used herein, unless otherwise indicated, refers to apartially saturated or saturated 4- to 10-membered monocyclic ring,fused ring, or bridged ring structure containing one or more heteroatomseach independently selected from N, O and S, preferably from one to fourheteroatoms. Non-exclusive examples of heterocycle include oxetanyl,azetidinyl, thiatanyl, tetrahydrofuryl, pyranyl, pyrazolidinyl,oxazolidinyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl,tetrahydropyridinyl, 2H-azirinyl, 2,3-dihydro-azetyl,3,4-dihydro-2H-pyrrolyl, and the like. The heterocycle group may beattached to the chemical moiety by any one of the carbon atoms ornitrogen heteroatoms within the ring. Further when used in compoundwords such as alkylheterocycle (e.g., C₀-C₄alkylheterocycle), said alkyland heterocycle moiety have the same meaning as herein defined and maybe attached to the chemical moiety by any one of the carbon atoms of thealiphatic chain. For example, C₀heterocycle is heterocycle (e.g.,(piperidinyl, morpholinyl, azetidinyl, and the like); C₁alkylheterocycleis —CH₂heterocycle (e.g., —CH₂morpholinyl, and the like),C₂alkylheterocycle is —CH₂CH₂heterocycle (e.g., —CH₂CH₂pyrrolidinyl,—CH₂CH₂thiomorpholinyl, and the like), and the like. Heterocycles areoptionally substituted as defined herein.

“Macrolide(s)”, as used herein, unless otherwise indicated, refers tocompounds characterized by a large lactone ring containing from 12 to 16carbon atoms to which are attached, via glycosidic bonds, one or moredeoxy sugars; and includes the class of azalides.

“Optionally substituted”, is used herein interchangeably with the phrasesubstituted or unsubstituted. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and each substitution is independent of the other. Anoptionally substituted group also may have no substituents. Therefore,the phrase “optionally substituted with at least one substituent” meansthat the number of substituents may vary from zero up to a number ofavailable positions for substitution. In the case of R⁹ and R¹⁰, atleast one optional substitution means that the number of substitutionsmay vary from zero to three (i.e., n is the integer 0, 1, 2 or 3), whichalso depends on the number of available positions for substitution.

“Pharmaceutically acceptable” as used herein, unless otherwiseindicated, indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, composition, and/or the animal being treatedtherewith. The term “pharmaceutically” or “pharmaceutical” has the samemeaning as that recited for “veterinarily” or veterinary.

“Protecting group” or “Pg”, as used herein, unless otherwise indicated,refers to a substituent that is commonly employed to block or protect analcohol on the compound thereby protecting its functionality whileallowing for the reaction of other functional groups on the compound.Non-exclusive examples of an alcohol-protecting group include:2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether(MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB),acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal(BOM), ethoxyethyl acetal (EE), methoxymethyl acetal (MOM),methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal(THP), triethylsilyl ether (TES), benzyloxycarbonyl (Cbz),triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS),tert-butyldimethylsilyl ether (TBS, TBDMS), and tert-butyldiphenylsilylether (TBDPS).

“Saturated” or “partially saturated”, as used herein, unless otherwiseindicated, refers to cycloalkyl rings having 3-6 carbon atoms andheterocyclic rings comprising 2-5 carbon atoms and at least oneheteroatom selected from N, O, and S; and wherein each saturated ringcontains single bonds between mutually adjacent carbon atoms or carbonheteroatoms; for example: cyclobutane, cyclopentane, cyclohexane,oxirane, oxetane, tetrahydofuran, piperadine, and the like. Partiallysaturated rings contain at least one double bond between mutuallyadjacent carbon atoms or carbon heteroatoms; for example: cyclobutene,cyclopentene, cyclohexa-1,3-diene, 2,3-dihydroazete, 2,5-dihydrofuran,2H-thiopyran, and the like.

“Stereoisomers”, as used herein, unless otherwise indicated, refers tothe compounds of the invention which have more than one asymmetriccarbon atom. In the general Formulas depicted herein, the solid wedgeshaped bond indicates that the bond is above the plane of paper and thebroken wedge bond indicates that the bond is below the plane of thepaper. The compounds of the invention may occur as individualenantiomers or diastereomers, or mixtures thereof, including racemicmixtures. All such isomeric forms are included within the presentinvention.

“Stress” or “stressful”, as used herein, unless otherwise indicated, isa specific or non-specific response that varies in degree. Stressors areparticular events, experiences, or environmental stimuli that affect ananimal's health, that may be acute, chronic, disruptive, or perceived asuncontrollable. Non-exclusive examples of stressors in animal healthinclude: natural disasters (e.g., floods, fires, and earthquakes), majorlife events (e.g., relocation/transportation, weaning, maternal and herdseparation, comingling of animals from different sources, tail docking,needle teeth extraction, pain, feed and water deprivation and acute orchronic illness), and acute/chronic disruptions (e.g., temperature andhumidity variation, confinement, shipping, improper nutrition andhydration, storms, loud noises (e.g., thunder, barking, fireworks, andthe like), environmental changes and pollutants, and the like).

“Therapeutically effective amount”, as used herein, unless otherwiseindicated, refers to an amount of a compound of the invention that (i)treats or prevents the particular disease or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease or disorder, or (iii) prevents or delays the onset of one ormore symptoms of the particular disease or disorder.

“Treatment”, “treating”, and the like, as used herein, unless otherwiseindicated, refers to control, preventative measures, reversing,alleviating, mitigating, or inhibiting inflammation driven by anenvironmental, bacterial-, viral-, fungal-, or parasitic-infection,and/or internal disease by moderating an immunological response. As usedherein, these terms also encompass, depending on the condition of theanimal, preventing the onset of a disorder or condition, or of symptomsassociated with a disorder or condition, including reducing the severityof a disorder or condition or symptoms associated therewith. Treatmentcan also refer to administration of a compound of the invention to ananimal that is not at the time of administration afflicted with theinfection, immunological episode, or disease disorder or complex. Aswill be appreciated, it is not always possible to distinguish between“preventing” and “suppressing” a disease or disorder since the ultimateinductive event or events may be unknown or latent.

Other than in operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients or reaction conditions usedherein should be understood as modified in all instances by the term“about”.

The compounds of the present invention have several asymmetric centers.Compounds with asymmetric centers give rise to enantiomers (opticalisomers), diastereomers (configurational isomers) or both, and it isintended that all of the possible enantiomers and diastereomers inmixtures and as pure or partially purified compounds are included withinthe scope of this invention. The present invention is meant to encompassall steric forms of the compounds of the invention. The presentinvention includes all stereoisomers of compounds of the invention.

The independent syntheses of the stereomerically enriched compounds, ortheir chromatographic separations, may be achieved as known in the artby appropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates that arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers ordiastereomers are isolated. The separation can be carried out by methodswell known in the art, such as the coupling of a racemic mixture ofcompounds, followed by separation of the individual stereoisomers bystandard methods, such as fractional crystallization or chromatography.The coupling reaction is often the formation of salts using anenantiomerically pure acid or base.

The derivatives may then be converted to the pure stereomers by cleavageof the added chiral residue. The racemic mixture of the compounds canalso be separated directly by chromatographic methods using chiralstationary phases, which methods are well known in the art.Alternatively, any stereomers of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Syn thesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Macrolide Chemistry

The macrolides are known to have a strong binding affinity to the P-siteon the 50S subunit of the bacterial ribosome and to inhibit proteinsynthesis. Modification of the desosamine group of the macrolide blocksthis interaction by either modification of the dimethylamino group toblock the salt bridge and/or modification of the neighboring hydroxygroup affecting the hydrogen bond formed, thereby removing theantibacterial activity of said compounds of the invention. Althoughcladinose modifications have a comparatively smaller effect on thebacterial ribosome binding, they have the potential to affect thephysicochemical properties, pharmacokinetics and cell permeability ofthe compound. By modifying macrolide structure therefore sequesteringthe molecule from entering the bacteria or enhancing efflux from thebacteria reduces or eliminates anti-bacterial activity even with theability to bind the bacterial ribosome.

Lipophilicity

The lipophilicity of an organic compound can be described by a partitioncoefficient, log P, which can be defined as the ratio of theconcentration of the unionized compound at equilibrium between organicand aqueous phases. Generally speaking, more lipophilic compounds areless soluble in aqueous media. A negative value for log P means thecompound has a higher affinity for the aqueous phase (hydrophilic); whenlog P=0 the compound is equally partitioned between the lipid andaqueous phases; a positive value for log P denotes a higherconcentration in the lipid phase (lipophilic). Lipophilicity is a majordetermining factor in a compound's absorption, distribution in the body,penetration across vital membranes and biological barriers, metabolismand excretion. The compounds of the invention are lipophilic (log P˜0.503 to 5.96) which aid in their transport and absorption intorespiratory tissues, e.g., lungs.

Composition/Formulation

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulation, dragee-making, levigating, emulsifying,encapsulating, entrapping, lyophilizing processes or spray drying.Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morepharmaceutically acceptable carriers, which facilitate processing of theactive compound into preparations for administration to the animal inneed thereof. The formulations of the invention can be designed to beshort-acting, fast-releasing, long-acting, and sustained-releasing.Thus, the pharmaceutical formulations can also be formulated forcontrolled release or for slow release; and are dependent upon the routeof administration chosen.

Pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers (including water) are described,for example, in “Remington's Pharmaceutical Sciences” Mack Pub. Co., NewJersey (1991).

For BRD and SRD, pharmaceutical compositions are typically formulatedfor parenteral administration, e.g., in a liquid carrier or suitable forreconstitution into liquid solution or suspension for parenteraladministration. In general, such compositions typically comprise apharmaceutically acceptable carrier. Pharmaceutical carriers accordingto the invention can be sterile liquids, such as but not limited towater, saline solutions, aqueous dextrose solutions, aqueous glycerolsolutions; and/or oils, including petroleum, animal, vegetable orsynthetic origin, such as soybean oil, mineral oil, sesame oil and thelike. Suitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences” by E. W. Martin, 18th Edition. Thepharmaceutical compositions comprising a compound of the invention canbe administered orally, topically, parenterally (i.e., intramuscular,subcutaneous, intravenous, and intradermal injection). Thepharmaceutical compositions comprising a compound of the invention canalso be administered by intramammary and intra-uterine injection.

Pharmaceutical compositions and formulations as defined herein can beprepared by mixing a compound of the invention having the desired degreeof purity with one or more pharmaceutically acceptable carrier(s) in theform of lyophilized formulations or aqueous solutions. The term“carrier” refers to a diluent, excipient, or vehicle with which thecompound of the invention is administered. Pharmaceutically acceptablecarriers are generally nontoxic to recipients at the dosages andconcentrations employed, and include, but are not limited to: buffers(e.g., NaOH, KOH, HCl, phosphate, citrate and other organic acids (e.g.,for example citric acid, acetic acid, benzoic acid, malic, and thelike); antioxidants (e.g., butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), sodium metabisulfite, monothioglycerol, propylgallate, and the like); preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride,benzethonium chloride, phenol, n-butyl, t-butyl or benzyl alcohol,chlorobutanol, thimerosal's, alkyl parabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, andthe like); hydrophilic polymers (e.g., polyvinylpyrrolidone (PVP),polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid,polyacrylamides, xanthum gum, and the like); amino acids (e.g., glycine,glutamine, asparagine, histidine, arginine, lysine, and the like);chelating agents such as EDTA; monosaccharides, disaccharides, and othercarbohydrates including sugars such as sucrose, mannitol, trehalose orsorbitol, glucose, mannose, or dextrins; and salt-forming counter-ionssuch as sodium; metal complexes (e.g., Zn-protein complexes). Thecarrier can be a solvent or reconstitution medium or dispersion mediumcontaining, for example, water, ethanol, polyol (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like), andsuitable mixtures thereof. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, water, orphosphate buffered saline (PBS). Prolonged absorption of the injectablecompositions can be brought about by including in the composition anagent which delays absorption, for example, aluminum monostearate andgelatin.

Solutions or suspensions used for parenteral application typicallyinclude one or more of the following components: a sterile carrier suchas water for injection, saline solution, fixed oils, polyethyleneglycols, glycerin, propylene glycol, or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid, BHA, BHT, monothioglycerol or sodiumbisulfite; chelating agents such as ethylene-diaminetetraacetic acid;buffers such as acetates, citrates or phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid, citric acidor sodium hydroxide. Such preparations may be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic. Theformulations to be used for in vivo administration are generallysterile. Sterility may be readily accomplished, e.g., by filtrationthrough sterile filtration membranes, and radiation. The injectablecompositions can contain the active component (drug) in the amountsranging from about 1 to 250 mg/mL, and more preferably, inconcentrations ranging from about 1 to 100 mg/mL. Without limiting thescope of the compositional components, an injectable compositioncomprising a Formula (1) compound (e.g., free base), pharmaceuticallyacceptable salt thereof, (e.g., acetate) can be prepared by dissolvingthe compound (e.g., 1 to 25 mg/mL) in a composition comprising citricacid, propylene glycol, water and optionally an antioxidant (e.g.,monothioglycerol). As described herein, the composition can containabout 90% (±˜6%) of lactone A and 10% lactone B (±˜6%) of a Formula (1)compound, and preferably a non-antibacterial Table H compound. Saidcomposition can be administered by injection, (e.g., subcutaneous). ThepH of the composition can be adjusted, as needed, with NaOH and/or HCl.Methods for preparation of such formulations will be apparent to thoseskilled in the art and can be prepared in accordance with proceduresdescribed in U.S. Pat. No. 6,514,945.

For oral use, the pharmaceutical compositions of the present invention,may be administered, for example, in the form of tablets or capsules,powders, dispersible granules, or cachets, or as aqueous solutions orsuspensions. Oral compositions generally include an inert carrier or anedible carrier. They can be enclosed in gelatin capsules or compressedinto tablets. For oral administration, the therapeutic agents can becombined with carriers and used in the form of tablets, troches, orcapsules. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches, and the like can contain any of the followingingredients, or compounds of a similar nature; a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,primogel, sodium starch glycolate, or corn starch; a lubricant such asmagnesium stearate or stearates; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent.

Dosage

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose. More specifically, atherapeutically effective amount means an amount of a compound of theinvention that is effective to prevent, alleviate or amelioratesymptoms/signs of disease or prolong the survival of the animal beingtreated. The quantity of active component, which is a compound of theinvention, in the pharmaceutical composition and unit dosage formthereof, may be varied or adjusted widely depending upon the manner ofadministration, the potency of the particular compound and the desiredconcentration. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art. Generally, thequantity of active component will range between 0.01% to 99% by weightof the composition.

Generally, a therapeutically effective amount of dosage of activecomponent will be in the range of about 0.01 mg/kg to about 10 mg/kg ofbody weight, preferably about 0.02 mg/kg to about 1 mg/kg of bodyweight, more preferably about 0.04 mg/kg to about 0.8 mg/kg of bodyweight, even more preferably about 0.06 mg/kg to about 0.6 mg/kg of bodyweight. A preferred dosage regimen is parenteral administration of about0.05 mg/kg to about 0.8 mg/kg of body weight by subcutaneous injection.It is to be understood that the dosages may vary depending upon therequirements of each animal and the severity of the disorders ordiseases being treated. The desired dose may conveniently be presentedin a single dose or as divided doses administered at appropriateintervals during the course of treatment. The preferred route ofadministration is parenteral. Parenteral administration includesintravenous, intramuscular, and subcutaneous injection. The preferredroute of administration is by subcutaneous injection. The compounds ofthe invention can be administered to the animal at first signs of stressor bacterial infection, prior to shipment from a farm or ranch, or uponarrival to the feed lot.

A compound of the invention can be administered in a pharmaceuticallyacceptable form either alone or in combination with one or moreadditional agents which modulate a mammalian immune system or withanti-inflammatory agents or with one or more antibacterial agents.Additionally, the compounds of the invention can also be co-administeredwith vitamins and/or minerals. Non limiting examples ofanti-inflammatory agents include: ketoprofen, cyclosporin A, rapamycin,FJ-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate,azathioprine, daclizumab, aspirin, acetaminophen, ibuprofen, naproxen,piroxicam, and anti-inflammatory steroids (e.g. prednisolone ordexamethasone). Non limiting examples of antibacterial agents include:novobiocin, aminoglycosides (e.g., gentamicin, neomycin,dihydrostreptomycin, spectinomycin, etc.), florfenicol, ceftiofur,cephapirin, ormetoprim, danofloxacin, enrofloxacin, bambermycins,ionophores (e.g., laidlomycin, lasalocid, monensin, narasin,salinomycin, lincomycin, pirlimycin, macrolides (e.g., erythromysin,gamithromycin, tildipirosin, tilmicosin, tulathroymycin, theM9-metabolite of tulathromycin, tylosin, tylvalosin, etc.), avilamycin,penicillins (e.g., amoxicillin, ampicillin, cloxacillin, penicillin,etc), tiamulin, polymyxin B, bacitracin, carbadox, virginiamycin,sulfadimethoxine, sulfamethazine, chlortetracycline, oxytetracycline,and tetracycline. Non-limiting examples of minerals include: calcium,magnesium, phosphorus, potassium, sodium, sulfur, cobalt, sulfur,copper, iodine, iron, manganese, selenium, chromium, and zinc.Non-limiting examples of vitamins include: A, D, E, K, and B vitaminsincluding: thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid(B5), pyridoxine (B6), biotin (B7) folate (B9), and B12. Theseadditional combination agents may be administered as part of the same orseparate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard medical or veterinary practice known to oneskilled in the art.

Medical and Veterinary Uses

Methods defined herein are generally performed on an animal in needthereof. An animal in need can be an animal having, diagnosed with,suspected of having, or at risk for developing a disease, disorder, orcondition associated with a bacterial infection, viral infection,parasitic infection, inflammation or an immune response. The disease ordisorder can include respiratory disease, reproductive diseases likemastitis or metritis, inflammatory bowel disease, bovine viral diarrheavirus (BVDV), infectious bovine thinotracheitis (IBR), bovinerespiratory syncytial virus (BRSV), parainfluenza virus, bovinecoronavirus, psoriasis, multiple sclerosis, rheumatoid arthritis,allergic autoinflammatory disease, or an autoimmune disease. Generally,a safe and effective amount of a compound of the invention is, forexample, that amount that would cause the desired therapeutic effect inan animal while minimizing undesired side effects. In variousembodiments, an effective amount of a compound of the invention cansubstantially mitigate inflammation or an immune response, slow theprogress of a disease, disorder, or condition associated withinflammation or an immune response, or limit the development of adisease, disorder, or condition associated with inflammation or animmune response.

Compounds of the invention are macrolide (azalide) analogues that lackantibacterial activity against BRD pathogens and have been shown to haveimmunomodulatory properties that prevent and/or control the symptoms ofBRD in artificially infected cattle. Accordingly, these macrolides areuseful therapeutic agents for treating and/or controlling respiratoryillnesses that may be provoked by environmental stimuli, stress, andbacterial infection. Some non-limiting macrolides used to treat BRDinclude: Draxxin© (tulathromycin), Zuprevo© (tildipirosin), and Zactran©(gamithromycin), and the like.

Draxxin©, an injectable solution, is indicated for the treatment ofbovine respiratory disease (BRD) associated with Mannheimia haemolytica,Pasteurella multocida, Histophilus somni, and Mycoplasma bovis; and forthe control of respiratory disease in cattle at high risk of developingBRD associated with Mannheimia haemolytica, Pasteurella multocida,Histophilus somni, and Mycoplasma bovis. Cattle receive a 2.5 mg/kgsubcutaneous dose of Draxxin©. In swine, Draxxin© is indicated for thetreatment of swine respiratory disease (SRD) associated withActinobacillus pleuropneumoniae, Pasteurella multocida, Bordetellabronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae; andfor the control of SRD associated with Actinobacillus pleuropneumoniae,Pasteurella multocida, and Mycoplasma hyopneumoniae in groups of pigswhere SRD has been diagnosed. Swine receive a 2.5 mg/kg intramuscularinjection of Draxxin©.

A compound of the invention can treat, reduce, or prevent a disease,disorder, or condition associated with inflammation or an immuneresponse. Inflammation is a critical response to potential dangersignals and damage in organs of the body. Commonly referred to as theinflammatory cascade, can be acute or chronic. Acute inflammation, partof the immune response, is the body's immediate response to injury orassault due to physical trauma, infection, stress, or a combination ofall three. Acute inflammation helps to prevent further injury andfacilitates the healing and recovery process. When inflammation becomesself-perpetuating however, it can result in chronic or long-terminflammation.

Trauma, inflammation, or infection leads to the activation of theinflammatory cascade. Initially, a proinflammatory activation occurs,but almost immediately thereafter a reactive suppressinganti-inflammatory response occurs. This systemic inflammatory response(SIR) usually manifests itself as increased systemic expression of bothproinflammatory and anti-inflammatory species. Systemic inflammatoryresponse starts with inflammation as a response to exogenous (microbial,physical, or chemical) agents or endogenous (immunologic or neurologic)factors. The response is initiated when inflammatory cells at the siteof inflammation, such as macrophages, are activated and rapidly produceTNF-α and IL-1. These cytokines in turn activate the cytokine cascaderesulting in the generation of pro-inflammatory cytokines, IL-6, andIL-8, as well as other chemokines. Inflammatory stimuli also trigger thesynthesis of anti-inflammatory cytokines and specific cytokineinhibitors to control the extent of the inflammatory response.Anti-inflammatory cytokines such as IL-4, IL-10, IL-11, and IL-13inhibit the synthesis of proinflammatory cytokines while the naturallyoccurring proinflammatory cytokine inhibitors neutralize proinflammatorycytokine activity by binding to pro-inflammatory cytokine receptors,decoy receptor antagonist, and cytokine binding proteins. The interplayamong these proinflammatory cytokines, anti-inflammatory cytokines, andnaturally occurring cytokine inhibitors determines the inflammatoryresponse and its effectiveness to contain the inflammatory response andbring about resolution of the initiating process. The main knownmediators involved in the evolution of SIRS are cytokines, nitric oxide,platelet activating factor (PAF), and eicosanoids. The systemic responseto infection is mediated via macrophage-derived cytokines that targetend organ receptors in response to injury or infection. However,production of anti-inflammatory protein and lipid molecules will alsotake place to attenuate and halt the inflammatory response. Thesemediators initiate overlapping processes that directly influence theendothelium, cardiovascular, hemodynamic, and coagulation mechanisms. Ifa balance between pro- and anti-inflammatory substances is notestablished and homeostasis restored, a massive pro-inflammatoryreaction (i.e. SIRS) and multiple organ dysfunction (MODS) may ensue.Thus, after the first pro-inflammatory mediators are released, the bodymounts a compensatory anti-inflammatory reaction to the initialinflammatory response. The anti-inflammatory reaction may be as robustand sometimes even more robust than the proinflammatory response. Inaddition to pro-inflammatory cytokines, other mediators such as NO, PAF,prostaglandins, and leukotrienes are also produced. These molecules areresponsible for activating complement, coagulation, and kinin cascadesas well.

Diseases associated with inflammation or an immune response can include:for example, but not limited to: bacterial infection; viral infection;fungal infection; parasitic infection; asthma; allergy; age relatedmacular degeneration; dermatitis; pain; mastitis; metritis;autoinflammatory disease; autoimmune disease; inflammatory boweldisease; dermatitis, multiple sclerosis; osteoarthritis; osteoporosis;psoriasis; rheumatoid and osteoarthritis arthritis; synovitis, acne,pustulosis, hyperostosis, airway and respiratory diseases (e.g., equineairway disease and canine infectious respiratory disease); respiratorydisease complex (bovine and swine), ischaemia-reperfusion, felinechronic kidney disease, feline and canine degenerative mitral valvedisease (inflammatory complex; e.g., pro-inflammatory cytokines in heartfailure via up-regulation of valvular and myocardial expression ofcytokines, chemokines and adhesion molecules), psoriasis, multiplesclerosis, rheumatoid arthritis autoinflammatory disease, peptic ulcers,tuberculosis, periodontitis, otitis, ulcerative colitis, Crohn'sdisease, lupus, sinusitis, hepatitis, coeliac disease, pelvicinflammatory disease, glomerulonephritis, transplant rejection, chronicobstructive pulmonary disease, gout, ankylosing spondylitis, myositis,laminitis, gingivitis, scleroderma, vasculitis, malaria, Lyme,babesiosis, ehrlichiosis, anaplasmosis, tularemia, amebiasis,giardiasis, fascioliasis, fasciolopsiasis, elephantitis,cryptosporidiosis, leishmaniasis, microsporidiosis, trypanosomiasis,toxoplasmosis, and the like; and other inflammatory and immune diseasesand disorders. A compound of the invention can treat a disease,disorder, or condition associated with inflammation by modulatingcytokines, chemokines, and inflammatory markers, for example, IL6,IL-1β, NFκB, CSP136, LCN, CXCL8 (IL-8), TNFα, and induce TLR4 signaling.

Macrolide Immunomodulation

The chemistry of macrolides provides the basis to understand theirimmunomodulation effects. Macrolides are defined as cationic amphiphilicdrugs; cellular penetration is primarily determined by theirlipophilicity and cationic nature at physiological pH. Cellular membranepenetration by macrolides leads to depolarization of phospholipids,resulting in disposition of both drug and phospholipid into the cytosoland lysosomes, ultimately resulting in cellular state ofphospholipidosis. Polar association with phospholipids, primarilyphosphatidylcholine, within cells inhibits natural degradation byphospholipase enzymes; resulting in a reduction of primary cellsignaling components, like arachidonic acid, among others. The decreasein arachidonic acid is postulated to prevent the normal production ofthe eicosanoid metabolites including prostaglandins, thromboxanes,leukotrienes and lipoxins. Additionally, indirect inhibition of the COXfamily of inflammatory mediators, NFkB and AP-1 and their resultingpro-inflammatory cytokine production are observed. The reduced abilityfor cells to signal, both intra and extracellularly is context dependenton the host. In healthy animals, macrolide treatment has beendemonstrated to stimulate neutrophil and macrophage response upondisease stimulus. However, in the presence of an acute or chronicinflammation state, an inhibition or reversal of the inflammation isobserved.

Modulation of host defense by azithromycin and other macrolideantibiotics occurs through interaction with structural cells, such asepithelial or endothelial cells, smooth muscle cells or fibroblasts, aswell as with leukocytes (macrophages, poly-morphonuclear leukocytes orneutrophils, mononuclear leukocytes or monocytes, T cells and dendriticcells). Cellular accumulation of macrolides is a mechanism of passivetransport into cells which does not require cellular energy, carrierproteins, and is unsaturable. The mechanism is distinct from ribosomebinding associated with antibiotic activity and therefore unrelated. Asan example, azithromycin aglycone which demonstrates no antibioticactivity demonstrates a high level of induced phospholipidosis (J.Parnham et al./Pharmacology & Therapeutics 143 (2014) 225-245).Azithromycin penetrates the cell membrane bilayer and stabilizes themembrane, reducing fluidity and neutralizing phospholipid charge on theinner leaflet membrane. This results in reduced fatty acid release andliberation of enzymes bound by electrostatic charge to the membrane,resulting modulation of signaling pathways and inhibition of theactivation of transcription factors including AP-1 and NFκB. Thesignaling pathway most affected is likely dependent on the particularcell, its activation state and the stimulus by which it is activated.Molecules dependent on negatively charged phospholipids are alsoaffected. Azithromycin accumulates in lysosomes, modulating MPRtransport of enzymes and lipids and through lipid remodeling in thelysosome membranes. One of the well documented aspects is their abilityto moderate inflammatory responses as demonstrated by downregulation ofexacerbated cytokine production (IL-1β, TNF-α, IL-6) through the NFκBpathway and effects on granulocytes; and gene expression.

Immunological activity can also be assessed by analyzing CD163. CD163 isa scavenger receptor that binds hemoglobin/haptoglobin and is expressedon macrophages thought to be involved in innate immune sensing that aidsin the clearance of activated macrophages thus preventing oxidativedamage to tissue.

CD163 also functions as an innate immune sensor for gram-positive andgram-negative bacteria. Accordingly, a high CD163 expression inmacrophages is a characteristic of tissues responding to inflammation,considered a highly correlative biomarker of inflammation. Thescavenging of the oxidative and proinflammatory hemoglobin leading tostimulation of the heme-oxygenase-1 and production of anti-inflammatoryheme metabolites indicates that CD163 thereby indirectly contributes tothe anti-inflammatory response (Antioxid Redox Signal., Etzerodt et.al., 2013, 18(17), p. 2352-2363). CD163 may participate in the processleading to lung lesions in BRD. The expression of CD163 may also becorrelated to elevated levels of IL-6 as observed in BRD, CD163 surfaceexpression has been experimentally induced by 253+/−4.9% in monocytesand macrophages upon incubation with IL-6 (Journal of Leukocyte Biology;Buechler et al. vol. 67 January 2020; p. 97-103). Alternativelycross-linking of CD163 on alveolar macrophages with monoclonal antibodyinduced a protein tyrosine kinase-dependent signal that resulted in slowtype calcium mobilization, inositol triphosphate production andsecretion of IL-6 and GM-CSF (Journal of Leukocyte Biology; Van deHeuvel et al. vol. 66 November 1999; p. 858-866). The anti-inflammatoryimmune-modulating drug, tacrolimus, was shown to slightly increase theexpression of CD163 (PLOS ONE; Kannegleter, et. al., January, 2017; p.1-19); wherein a later study (HHS Public Access; Motta, et. al., OralDis. 2018, 24(4) p. 580-590) reported that therapy did not result inchanges in the expression of CD163. Similarly, azithromycin (BritishJournal of Pharmacology, Vrancic, et. al; 2012, 165; p. 1348-1360)reported enhanced expression of CD163. CD163 expression upregulatesglucocorticoids, IL-6, IL-10, and hemoglobin; and downregulates IL-4,IFN-γ, TNF-, CXCL4, and GM-CSF. In contrast, CD163 was suppressed incattle treated with M9 and H-91 correlating with the proposed mechanismof inflammatory state reduction.

Cytokines are considered to be in a broad and loose category of smallproteins (5-20 kDa) that are important in cell signaling. Their releasehas an effect on the behavior of cells around them. It can be said thatcytokines are involved in autocrine signaling, paracrine signaling andendocrine signaling as immunomodulating agents. Cytokines are generallyknown to include chemokines, interferons, interleukins, lymphokines, andtumor necrosis factors (TNF) but generally not hormones or growthfactors. Cytokines can be produced by a broad range of cells, includingimmune cells like macrophages, neutrophils, B lymphocytes, T lymphocytesand mast cells, as well as epithelial cells, endothelial cells,fibroblasts, and various stromal cells; a given cytokine may be producedby more than one type of cell. Cytokines can act through receptors andare especially important in the immune system. Cytokines can modulatethe balance between humoral and cell based immune responses, and theycan regulate the maturation, growth, or responsiveness of particularcell populations. Some cytokines can enhance or inhibit the action ofother cytokines in complex ways. Cytokines can be important in healthand disease, specifically in host responses to infection, immuneresponses, inflammation, stress, trauma, sepsis, cancer, andreproduction.

Interleukin 6 (IL-6) is a pleitropic cytokine that acts as both apro-inflammatory cytokine and an anti-inflammatory myokine. IL-6 isproduced and secreted by a variety of cells, including B cells, T cells,endothelial cells and macrophages to stimulate an immune response viathe classic signaling pathway when it binds to the transmembrane IL-6receptor (IL-6R) or via the trans-signaling pathway upon binding to thesoluble form of IL-6R (sIL-6R); during infection and after tissue traumaleading to inflammation. The trans-signaling is responsible for thepro-inflammatory actions and most of the pathological effects of IL-6.Dysregulation of the IL-6 pathway has been reported to associate withdevelopment of several disease states, including a variety ofinflammatory disorders. IL-6 is reported to induce vascular endothelialgrowth factor production, which enhances angiogenesis and increasesvascular permeability, a feature of several inflammatory disorders. IL-6is also implicated in enhancement of neutrophil, monocyte/macrophagerecruitment and blockade of anti-inflammatory T-regulatory cells. Inchronic inflammation, IL-6 has a detrimental role and leads tomononuclear cell accumulation at the site of injury. This may lead to anincrease in serum levels of IL-6 and sIL-6R providing a foundation forthe amplification step of chronic inflammatory responses. IL-6 has beenimplicated in the development of pulmonary neutrophilia by enhancingboth neutrophil recruitment from blood and bone marrow and neutrophilsurvival. IL-6's role as an anti-inflammatory cytokine is mediatedthrough its inhibitory effects on TNF-alpha and IL-1, and activation ofIL-1ra and IL-10.

IL-6, like other inflammatory cytokines, has been shown to be elevatedin different lung diseases in human and mice. IL-6 was elevated in thebovine BRD (M. hemolytica) challenge and was correlated with higherrectal temperature, lung lesions and mortality. The compounds of theinvention, M9, and tulathromycin significantly reduced IL-6 levels whichalso correlated with overall animal survival. Therefore, theimmune-modulatory compounds of the invention mitigate the pathologicincrease in IL-6 consistent with dose and clinical outcome.

IL-36 is a member of the IL-1 superfamily of cytokines and includesthree agonists (IL-36α, IL-36p, and IL-36γ) and an antagonist (IL-36RA).The IL-36 agonists bind to heterodimeric IL-36 receptor (IL-36R)complexes to produce a pro-inflammatory response. The antagonist bindsto the IL-36R thereby prohibiting IL-36 signaling. IL-36 signalingoccurs through the formation of a heterotrimeric complex IL-36, theIL-36R, and the IL-1AcP (IL-1 accessory protein) and activate theadaptor protein myeloid differentiated protein 88 (MyD88),mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B(NF-κB) signaling pathways and induce inflammatory responses. IL-36RAprevents the interaction between the IL-1AcP and the receptor ligandcomplex. IL-36 proteins are widely expressed in T cells, keratinocytes,and skin, lung, and gut cells. IL-36 agonists bind to receptors[IL-36Rand IL-1 receptor accessory protein (IL-1RAcP)] and then activate.Finally, these pathways initiate the regulation of target genes. Recentevidence suggests that IL-36 regulates the function of both non-immunecells and immune cells; and is involved in immune cell activation,antigen presentation, and pro-inflammatory factor production. IL-36 hasattracted great interest because of its dysregulation in inflammatorydiseases. For example, serum and tissue IL-36 expression was increasedin inflammatory and immune diseases and disorders like psoriasis,rheumatoid arthritis, and inflammatory bowel disease.

Chemokines

Chemokines are a family of small cytokines, or signaling proteinssecreted by cells. Their name is derived from their ability to inducedirected chemotaxis in nearby responsive cells (i.e., chemotacticcytokines); that stimulate recruitment of leukocytes. The main functionof chemokines is to manage the migration of leukocytes (homing) in therespective anatomical locations in inflammatory and homeostaticprocesses. They are secondary pro-inflammatory mediators that areinduced by primary pro-inflammatory mediators such as IL-1 or TNF. Thereare two major chemokine sub-families based upon the position of cysteineresidues, i.e., CXC and CC. All members of the CXC chemokine sub-familyhave an intervening amino acid between the first two cysteines; membersof the CC chemokine sub-family have two adjacent cysteines. As a generalrule, members of the CXC chemokines are chemotactic for neutrophils, andCC chemokines are chemotactic for monocytes and a small sub-set oflymphocytes. Some chemokines are considered pro-inflammatory and can beinduced during an immune response to recruit cells of the immune systemto a site of infection or tissue damage, while others are consideredhomeostatic and are involved in controlling the migration of cellsduring normal processes of tissue maintenance or development (e.g.,angiogenesis).

Inflammatory chemokines are formed under pathological conditions (onpro-inflammatory stimuli, such as IL-1, TNF-alpha, LPS, or viruses) andactively participate in the inflammatory response attracting immunecells to the site of inflammation and include: CXCL8 (IL-8), CCL2, CCL3,CCL4, CCL5, CCL11, CXCL10. These inflammatory chemokines are produced inhigh concentrations during infection or injury and determine themigration of inflammatory leukocytes into the damaged area. A typicalexample is CXCL8, which acts as a chemoattractant for neutrophils. Incontrast to the homeostatic chemokine receptors, there is significantpromiscuity (redundancy) associated with binding receptor andinflammatory chemokines.

Interleukin-8 (IL-8) is one of the proinflammatory chemokines thatattract and activate immune and inflammatory cells. IL-8 mediates anarray of biological effects, including several involving neutrophils:inflammatory cell activation and chemotaxis, production of reactiveoxygen species, increased expression of the integrin CD11b-CD18,enhancement of cell adhesion to endothelial cells, promotion ofangiogenesis, and modulation of histamine release. IL-8 is produced bymany cells, including neutrophils, monocytes, macrophages, mast cells,vascular endothelial cells, stromal cells and epithelial cells inresponse to an innate exogenous/endogenous stimulus. In target cells,IL-8 induces a series of physiological responses required for migrationand phagocytosis, such as increases in intracellular Ca²⁺ and exocytosis(e.g. histamine release).

Recruitment of inflammatory cells, such as neutrophils in response totissue injury such as infection is a normal physiological response toeliminate the infectious agent, remove damaged or dead cells andinitiate the healing process. However, excessive recruitment of thesecells, the extended residence time and death of cells results in tissuedamage. Influx of excessive inflammatory cells is therefore thought tobe instrumental in the pathophysiology of pulmonary diseases such as inhuman inflammatory conditions such as chronic obstructive pulmonarydisease (COPD), acute respiratory distress syndrome (ARDS, asthma,pulmonary fibrosis and bacterial pneumonia. This has also been observedin bovine respiratory disease (BRD) and bacterial pneumonia. Control ofrecruitment and activation of these cells in the lung would be anattractive strategy for therapeutic intervention. In all theseconditions, IL-8 appears to be important for the recruitment andactivation of neutrophils and T cells into the respiratory tract.

In an experimental cattle challenge study with M. hemolytica, one of themajor causative agents of BRD, IL-8 levels were up-regulated in serumand tissues. The compounds of the invention were shown to downregulateIL-8 production in this challenge model and this correlated with amitigated anti-inflammatory response and disease.

Biology of BRD

It has been long believed that the pathobiology of BRD originates from astress-induced immune suppression leaving calves vulnerable to a myriadof microorganisms they encounter during the transition from cow-calfoperation to feedlot. The dogma suggests that stimulation of the innateimmune system would have a positive impact on the clinical outcome.However, to date, there has been little success with interventionsconsistent with this dogma, including the use of a DNA immunostimulant(Zelnate®). With the goal to better understand the progression of BRD,earlier studies suggest that it is the early unresolved heightenedinflammatory state rather than immunosuppression that leads to theprogression to BRD.

Based on current research driving BRD etiology, a novel understanding ofthe immunological status has shown that while a heightenedpro-inflammatory state is ubiquitous in at-risk cattle, the perpetuationor lack of resolution/mitigation of this state coincides with diseaseoutcome. After shipping on arrival to a feedlot, the pro-inflammatorystate is especially characterized by innate immune components such asnasal-mucosal epithelial cell barrier damage and the release ofpre-formed mediators such as members of the IL-1 cytokine family.Activation of danger-associated molecule patterns (DAMPs) includingpattern recognition receptor (PRR) TLR-4 and inflammasome signalingdemonstrate a response by epithelial and resident myeloid cells to theco-localized microbes in the upper airway. As bacterial components suchas lipopolysaccharides (LPS; lipoglycans and endotoxins) induce TLR4signaling, transcription factors such as NF-κB induce the expression ofkey cytokines involved in perpetuating the inflammatory process such asIL-1β, IL-6 and TNF-α and myeloid-derived granulocytes includingmacrophages and neutrophils are recruited and activated. These cascadeslead to an environment where bacteria normally limited to the upperairway can transgress into the lung and cause disease. Associated withclinical disease are biomarkers of inflammatory processes such aselevated levels of secreted cytokines like IL-6 and acute phaseproteins. Also associated with clinical disease are markers of cellularactivation, for example expression of the scavenger receptor CD163 onmacrophages and neutrophil-associated mediators such as LCN and CXCL8.The compounds of the invention effectively mitigates the heightenedpro-inflammatory state in at-risk cattle by equilibrating the immuneresponse and reducing the pathologic inflammatory cascade. Thismechanism of an immunomodulator in the context of BRD progression isdepicted in FIG. 1.

The compounds of the invention represent a new approach to a highlycomplex disease and have the potential to significantly reduce theincidence of BRD and the need for antibiotic treatment. They effectivelymoderate the pathologic innate inflammation occurring during theshipping period enabling the animal to restore homeostasis in atimeframe consistent with clinical disease protection.

Schemes and Experimentals

Within the schemes and experimental procedures presented herein, thefollowing acronyms are defined: benzyloxycarbonyl (Cbz); ON (overnight,16-24 hours); protecting group (Pg); leaving group (Lg); triethyl amine(TEA); dichloromethane (DCM); cyano (CN); tetrahydrofuran (THF);palladium on carbon (Pd/C); trifluoroacetic acid (TFA); acetic acid(AcOH); tert-butyl alcohol (t-BuOH or TBA); room temperature (RT); ethylacetate (EtOAc); dimethylformamide (DMF); N-methyl-2-pyrrolidine (NMP);methyl tert-butyl ether (MTBE); N,N-diisopropylethylamine (DIPEA);phenyl (Ph); and copper II acetate (Cu(OAc)₂).

Tulathromycin A is a 15-membered (lactone A) closed ring antibacterialmacrolide (azalide). The azalide converts to a 13-membered (lactone B)closed ring, tulathromycin B. This conversion is in an equilibrium ratioof about 9:1 (A:B), and is depicted below.

The tulathromycin azalides can also be represented by the followingstructures:

Tulathromycin is(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;and a precursor to tulathromycin, tulathromycin epoxide (tula-epx), is(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one.

In addition to the tulathromycin azalides (tulaA and tulaB) depictedjust above, the compound, lactone A and B of Example H-11 is shownbelow:

The H-11 lactones were separated by HPLC using an Agilent 1100quaternary pump and diode array detector (250 nm) with an X-select CSHC18 column (150×4.6 mm, 2.5 μm) at 50° C. using a gradient mobile phase(mp) comprising 0.03% H₂SO₄ in water (mpA) and acetonitrile (mpB) over16 minutes. Lactone A eluted at 5.8 minutes (area % 92.4) and lactone Beluted at 5.2 minutes (area % 7.6).

In an aqueous solution, Example H-11 exists as an equilibrated mixtureof two lactone isomers as shown above. The ratio is approximately 9:1lactone A:B. The rate of equilibration depends on pH and temperature,with neutral pH giving faster equilibration, pH ˜5-6 giving much slowerequilibration, and higher temperatures resulting in fasterequilibration. Equilibration occurs in under 1-hour at pH>6 andtemperatures >60° C. H-11 isomerization is a 6 exo-Trig cyclization andis a favored reaction by Baldwin's Rules. The dominant isomer,lactone-A, is a 15-membered macrocyclic lactone, while the minor isomer,lactone-B, is a 13-membered macrocyclic lactone. H-11 exhibits pHdependent aqueous solubility, where it is very soluble at acidic pHunder acidic conditions and has a lower solubility as the pH approachesneutral conditions. Due to the pH dependent solubility of H-11, andother compounds of the invention, dissolution of an organic acid (e.g.,citric acid) into water prior to adding the active agent (e.g., H-11)may be necessary to ensure complete dissolution, particularly for higherconcentration solutions, thereby providing a solution with enoughbuffering capacity for dissolution.

One of the metabolites of tulathromycin A is the des-methyl azalide,(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)-tetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one(M9), depicted in the following diagrams below:

Tulathromycin B also metabolizes to the B-des-methyl azalide.

The M9 analogue can be used as a starting material for preparingcompounds of the invention. The process to make des-methyl tulathromycin(M9) is a two-step process from tulathromycin A and the intermediate isgenerally not isolated, but it can be. The first step is an oxidation ofthe tertiary amine to the N-oxide using any number of oxidizing agentsknown to oxidize tertiary amines. The second step is a Polonovski-typedemethylation which can employ any metal known to effect that type oftransformation. It's generally iron, but a copper salt (Cu(II)) can alsobe used.

To a cold (<0° C.) solution of tulathromycin A (4.0 g, 5.0 mmol) inn-butanol (20 mL), 1.22 g (5.1 mmol) of a commercial 32% peracetic acidsolution was added. After 30 minutes, the product was extracted into a0.25M aqueous solution of disodium ethylenediamine-tetraacetic acid(EDTA, 15 mL). The aqueous solution was basified to pH 9.5 withconcentrated aqueous ammonia and extracted with tert-butyl methyl ether(20 mL). The N-oxide product was concentrated to a thick oil but was notisolated, [M+H]⁺=822. The oil was dissolved in methanol (16 mL).Copper(II) sulfate pentahydrate (1.5 g, 6.1 mmol) and acetic acid (0.28mL) were added and the reaction was heated to 60° C. for 1-2 hours. Thesolution was cooled to 25° C. and hydroxylamine hydrochloride (0.75 g,10 mmol) in water (8 mL) was added. After 2 hours, the product waspartitioned between water (28 mL, adjusted to pH 9.5 with aqueousammonia) and methylene chloride (20 mL). The organics were concentratedto an oil and the product was crystallized from hot acetonitrile (40mL). The resulting white crystalline powder was dried to provide 3.2 gof M9. LCMS [M+H]⁺=792.5. HPLC purity >98%. ¹H NMR (600 MHz, d₆-DMSO):N-Me (3H, 2.42 ppm, S) compared to tulathromycin NMe₂ (6H, 2.26 ppm).

Alternatively, M9 can be prepared by mixing a 20° C. solution oftulathromycin A (4.0 g, 5.0 mmol) in n-butanol (10 mL) and then addhexafluoroacetone trihydrate (0.27 g, 1.2 mmol) followed by 30% aqueoushydrogen peroxide (0.62 g, 5.5 mmol). After 4 hours, acetic acid (0.31g, 5.5 mmol) was added followed by methyl tert-butyl ether (6 mL) andwater (25 mL). The upper organic layer was discarded. Methyl tert-butylether (8 mL) was added and the pH of the aqueous layer was adjusted to9.8 with aqueous ammonia. The lower aqueous layer was discarded. TheN-oxide product was concentrated to a thick oil but was not isolated.[M+H]⁺=822. The oil was dissolved in methanol (12 mL). Anhydrouscopper(II) sulfate (0.97 g, 6.1 mmol) and acetic acid (0.28 mL) wereadded and the reaction was heated to 60° C. for 1 hour. The solution wascooled to 25° C. and hydroxylamine hydrochloride (0.75 g, 10 mmol) inwater (8 mL) was added. After 2 hours, the product was partitionedbetween water (28 mL, adjusted to pH 9.5 with aqueous ammonia) andmethylene chloride (20 mL). The organics were concentrated to an oil andthe product was crystallized from hot acetonitrile (40 mL). Theresulting white crystalline powder was dried to provide 3.2 g ofproduct; LCMS [M+H]⁺=792.5. HPLC purity >98%. 1H NMR (600 MHz, d6-DMSO):N-Me (3H, 2.42 ppm, S) compared to tulathromycin NMe₂ (6H, 2.26 ppm).

Alternatively, M9 can be prepared by mixing a solution of an epoxideprecursor of Tulathromycin A,(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one(tula-epx), (20.0 g, 27 mmol) in methanol (40 mL) and then add aceticacid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol)and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol).

After 4 hours at 35° C., the reaction was cooled to 20° C. and anhydrouscopper(II) sulfate (4.5 g, 29 mmol) was added and the reaction washeated to 60° C. for 1 hour. After cooling to 20° C., added 60 mLmethylene chloride and 80 mL water. Basified the mixture toapproximately pH 9.8 with concentrated aqueous ammonia. Concentrated theorganics under vacuum to a solid and then added 2-propanol (40 mL) andn-propylamine (40 mL). Heated to 65° C. and stirred for 15 hours.Concentrated under vacuum to remove solvents. Added acetonitrile (120mL) and heated to 78° C. Cooled to 10° C. and isolated product byfiltration. The resulting white crystalline powder was dried to provide12 g of product; LCMS [M+H]⁺=792.5. HPLC purity >98%. 1H NMR (600 MHz,d6-DMSO): N-Me (3H, 2.42 ppm, S) compared to tulathromycin NMe₂ (6H,2.26 ppm).

Azithromycin (depicted below), an azalide similar to tulathromycin,except the core ring N is substituted with a methyl group (1′) and thecladinose sugar is not further substituted with methylpropanamine (2′);depicted below.

Azithromycin can be derivatized to prepare a des-methyl analogue,similar to M9. Further derivatizations can be conducted in accordancewith the schemes and experimentals defined herein to prepareimmune-modulating azithromycin derivatives that are not active (i.e.,non-antibacterial) against BRD bacterial pathogens. In addition toazithromycin, other macrolides, for example, erythromycin, tilmicosin,clarithromycin, gamithromycin, fidaxomicin, roxithromycin,telithromycin, dirithromycin, josamycin, midecamycin, oleandomycin,roxithromycin, and others, can be modified in a similar manner as M9 toprepare immune-modulating analogues that lack antibacterial propertiesagainst BRD and other bacterial pathogens in animals, including humans.

For illustrative purposes, the reaction schemes depicted belowdemonstrate potential routes for synthesizing key intermediates andcompounds of the invention. For a more detailed description of theindividual reaction steps, see the Examples section below. Those skilledin the art will appreciate that other suitable starting materials,reagents, and synthetic routes may be used to synthesize theintermediates and compounds of the invention and a variety ofderivatives thereof. Further, many of the compounds prepared by themethods described below can be prepared and/or modified usingconventional chemistry.

The compounds of the invention may be used in its native form or as asalt. In cases where forming a stable nontoxic acid salt is desired,administration of the compound as a pharmaceutically acceptable salt maybe appropriate. For the purpose of the present invention, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical evaluation, suitable for use incontact with the tissues and organs of animals without displayingtoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Further, thecompounds of the invention have a secondary or tertiary amine group,which has basic character and thus can form acid addition salts, whichmay be pharmaceutically acceptable acids. Therefore, pharmaceuticallyacceptable salts according to the present invention include thosepharmaceutically acceptable acid addition salts formed with organic andinorganic acids and those pharmaceutically acceptable salts formed withoptically active acids. Representative acid addition salts include, butare not limited to, acetate, adipate, alginate, ascorbate, citrate,aspartate, benzoate, benzenesulfonate, besylate, bicarbonate/carbonate,bisulfate/sulfate, borate, butyrate, camphorate, camphorsulfonate,camsylate, citrate, digluconate, edisylate, etoglutarate, esylate,formate, fumarate, gluceptate, gluconate, glucuronate, glutamate,glycerophosphate, hemisulfate, heptanoate, hexafluorophosphate,hexanoate, hibenzate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, pectinate,persulfate, phosphate/hydrogen phosphate/dihydrogen phosphate, picrate,pivalate, proprionate, saccharate, stearate, succinate, tartrate,thiocyanate, tosylate and trifluoroacetate salts.

In the following Schemes, the demethylation or Polonovski reactionoccurs when an amine oxide reacts with an acylating agent. The acceptedmechanism involves proton removal to give a nitrogen ylide which losesacetate (using acetic anhydride) which attacks the carbon adjacent tothe nitrogen atom giving an α-acetoxyamine. The central feature of thePolonovski reaction is the transformation of an N-oxide to an iminiumion intermediate. Depending on the structure of the substrate and theacid anhydride or other activating reagent employed, iminium ionformation can occur through loss of an α hydrogen, or throughfragmentation of a Ca-carbon bond. Again, depending on conditions, thereaction will either stop at this stage and iminium ions become thePolonovski products, or proceed to give enamines or tertiary amidesand/or secondary amines and aldehydes.

In principle, any reagent capable of activating the N-oxide oxygentowards iminium ion formation thus triggering the Polonovski reactioncan be used. However, three major types of activating agents, acidanhydrides and chlorides (including chloroformate esters), iron orcopper salts and complexes, and sulfur dioxide, can be employed.

In the following Schemes and preparations, the following acronymsinclude: methanol (MeOH), ethanol (EtOH), dichloromethane (DCM),trifluoroacetic acid (TFA), hydrogen peroxide (H₂O₂), potassium cyanide(KCN), triethylamine (TEA), triethylamine trihydrofluoride (TEA.3HF),dimethylformamide (DMF), potassium cyanide (KCN),N,N-diisopropylethylamine (DIPEA), dichloroethane (DCE), isopropylalcohol (IPA), ethylenediaminetetraacetic acid (EDTA), acetic acid(AcOH), ammonium hydroxide (NH₄OH), acetonitrile (MeCN or Acn), sodiumtriacetoxyborohydride (STAB), sodium methoxide (MeONa), cerium(III)chloride (CeCl₃), sodium azide (NaN₃), sodium bicarbonate (NaHCO₃),ammonium chloride (NH₄Cl), magnesium sulfate (MgSO₄), bromine (Br²),sodium sulfate (Na₂SO₄), ammonium sulfate ((NH₄)₂SO₄), copper sulfate(CuSO₄), sodium cyanoborohydride (NaBH₃CN), 1-butanol (N-BuOH),hexafluoroacetone ((CF₃)₂CO—H₂O), methoxy (OMe), ethoxy (OEt), roomtemperature (RT), overnight (ON) and water (H₂O).

The urea analogs can be prepared following the 3-step procedure outlinedin Scheme 1a above. First, the commercially available tulathromycinepoxide (tula-epx) can be demethylated under but not limited to thePolonovski reaction to give M9 epoxide (M9-epx). The N-oxide can beformed using different oxidizing agents such as iodine,N-iodosuccinimide, peracetic acid or hydrogen peroxide. Thedemethylation of the N-oxide can be triggered with iron or copper salts.The secondary amine thus formed can be transformed into various ureasusing urea forming reagents such as isocyanates; activatedcarbamoyl-chlorides, -imidazoles, —N-methyl imidazoles; p-NO₂ phenolesters and others. Mild bases such as TEA or DIPEA can be sometimes usedto facilitate the urea formation reaction. Non-limiting examples ofleaving groups (LG) include chlorine, imidazole, methyl-imidazole,p-NO₂-phenol, and the like. In the last step, the epoxide functionalgroup can be opened to give the final urea analogs using differentnucleophiles such as primary and secondary amines, alcohols, thiols,cyanide, azide or halogen anions and others at higher temperature inalcoholic solvents such as but not limited to 1-propanol, 1-butanol or2-propanol. This reaction can be completed overnight. Mild bases such asNaHCO₃ or salts such as NH₄Cl or (NH₄)₂SO₄ can sometimes accelerate theepoxide opening reaction. For any of the Schemes presented herein, the“nucleophile” of the epoxide opening step on the cladinose ring, can beone of the following but not limited to the following: HNR⁵R⁶, HOR⁷,HS(O)_(p)R⁷, NaN₃, CeCl₃, TEA.3HF, and KCN, wherein R⁵, R⁶, R⁷ and p areas defined herein.

For the (s1b-A1) analogs, the epoxide functional group can be opened togive the final urea analogs using different primary or secondary aminesin alcoholic solvents such as but not limited to methanol, ethanol,1-proponaol and others. For the (s1b-A2) analogs, the epoxide functionalgroup can be opened to give the final urea analogs using differentalcohols used as solvents such as but not limited to methanol, ethanol,1-proponaol and others. Mild bases such as NaHCO₃ or salts such as NH₄Clor (NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction. Forthe (s1b-A3) analogs, the epoxide functional group can be opened to givethe final urea analogs using different thiols such as but not limited toethanethiol, propanethiol, isopropyl mercaptan and others in alcoholicsolvents such as but not limited to ethanol or 1-propanol. Mild basessuch as NaHCO₃but not limited to are used to accelerate the epoxideopening reaction. For the (s1b-A4) analogs, the epoxide functional groupcan be opened to give the final urea analogs using different halidesfrom reagents such as but not limited to CeCl₃ or Br₂ in alcoholicsolvents such as but not limited to ethanol or 1-propanol. Mild basessuch as NaHCO₃ or salts such as NH₄Cl or (NH₄)₂SO₄ can sometimesaccelerate the epoxide opening reaction. For the (s1b-A5) analogs, theepoxide functional group can be opened to give the final urea analogsusing different sources of the azide anion such as but not limited toNaN₃ in alcoholic solvents such as but not limited to ethanol or1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Cl or(NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction. For the(s1b-A6) analogs, the epoxide functional group can be opened to give thefinal urea analogs using different sources of the cyanide anion such asbut not limited to KCN in alcoholic solvents such as but not limited toIPA or 1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Cl or(NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction.

Alternatively, the urea analogs can be prepared according to Scheme 2a.In the first step, the commercially available tulathromycin epoxideintermediate is treated with various nucleophiles such as but notlimited to primary and secondary amines, alcohols, thiols, cyanide,azide or halogen anions and others at higher temperature in alcoholicsolvents such as but not limited to 1-propanol, 1-butanol or 2-propanol.This reaction can occur overnight. Mild bases such as NaHCO₃ or saltssuch as NH₄Cl or (NH₄)₂SO₄ can sometimes accelerate the epoxide openingreaction. In the second step, the tertiary dimethyl amine on thedesosamine sugar can be demethylated using Polonovski type conditions asdescribed above. The final urea analogs can be prepared by reacting thesecondary methyl amine moiety with urea forming reagents such as but notlimited to isocyanates; activated carbamoyl-chlorides, -imidazoles,—N-methyl imidazoles; p-NO₂ phenol esters, and the like.

For the (s2b-A1) compounds, the epoxide functional group can be openedusing different primary or secondary amines in alcoholic solvents suchas but not limited to methanol, ethanol, 1-proponaol and others. For the(s2b-A2) compounds, the epoxide functional group can be opened usingdifferent alcohols used as solvents such as but not limited to methanol,ethanol, 1-proponaol and others. Mild bases such as NaHCO₃ or salts suchas NH₄Cl or (NH₄)₂SO₄ can sometimes accelerate the epoxide openingreaction. For the (s2b-A3) compounds, the epoxide functional group canbe opened using different thiols such as but not limited to ethanethiol,propanethiol, isopropyl mercaptan and others in alcoholic solvents suchas but not limited to ethanol or 1-propanol. Mild bases such asNaHCO₃but not limited to are used to accelerate the epoxide openingreaction. For the (s2b-A4) compounds, the epoxide functional group canbe opened using different halides from reagents such as but not limitedto CeCl₃ or Br₂ in alcoholic solvents such as but not limited to ethanolor 1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Cl or(NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction. For the(s2b-A5) compounds, the epoxide functional group can be opened by theazide ion using different sources of the azide anion such as but notlimited to NaN₃ in alcoholic solvents such as but not limited to ethanolor 1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Cl or(NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction. For the(s2b-A6) compounds, the epoxide functional group can be opened by thecyanide ion using different sources of the cyanide anion such as but notlimited to KCN in alcoholic solvents such as but not limited to IPA or1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Cl or(NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction.

All compounds (s2b-A1) through (s2b-A6) can undergo a Polonovski typedemethylation as described above, to give the corresponding compounds(s2c-A1) through (s2c-A6). The N-oxide can be formed using differentoxidizing agents such as iodine, NIS, peracetic acid or hydrogenperoxide. The demethylation of the N-oxide can be triggered by suchreagents as iron or copper salts.

In the last step of the sequence the final analogs can be prepared byreacting the Polonovski reaction product (s2c-A#) with urea formingreagents such as but not limited to isocyanates; activatedcarbamoyl-chlorides, -imidazoles, —N-methyl imidazoles; p-NO₂ phenolesters, and the like. Details of this last transformation are shown inScheme 2d above.

Alternatively, the analogs can be prepared as depicted in Scheme 3a. Inthe first step, the commercially available tulathromycin epoxide can bedemethylated under but not limited to the Polonovski reaction asdescribed above. M9-epoxide thus formed can be reacted with variousnucleophiles such as but not limited to primary and secondary amines,alcohols, thiols, cyanide, azide or halogen anions and others at highertemperature in alcoholic solvents such as but not limited to 1-propanol,1-butanol or 2-propanol to open up the epoxide moiety. Mild bases suchas NaHCO₃ or salts such as NH₄Cl or (NH₄)₂SO₄ can sometimes acceleratethe epoxide opening reaction. The details of this second step are shownbelow in Scheme 3b. In the last step, The final urea analogs can beprepared by reacting the secondary methyl amine moiety with urea formingreagents such as but not limited to isocyanates; activatedcarbamoyl-chlorides, -imidazoles, —N-methyl imidazoles; p-NO₂ phenolesters, and the like. Details of this last transformation are shown inScheme 3c below.

M9-epoxide formed from the demethylation of the commercially availabletulathromycin epoxide (Scheme 3a) can be reacted to give the followingcompounds with Formula: (s3b-A1)—with various primary or secondaryamines in alcoholic solvents such as but not limited to methanol,ethanol or 1-propanol; (s3b-A2)—with various alcohols used as solventsuch as but not limited to methanol, ethanol or 1-propanol. Mild basessuch as NaHCO₃ or salts such as NH₄Cl or (NH₄)₂SO₄ can sometimesaccelerate the epoxide opening reaction; (s3b-A3)—with various thiolssuch as but not limited to ethanethiol, propanethiol, isopropylmercaptan and others in alcoholic solvents such as but not limited toethanol or 1-propanol. Mild bases such as but not limited to NaHCO₃areused to accelerate the epoxide opening reaction; (s3b-A4)—with halidesfrom reagents such as but not limited to CeCl₃ or Br₂ in alcoholicsolvents such as but not limited to ethanol or 1-propanol. Mild basessuch as NaHCO₃ or salts such as NH₄Cl or (NH₄)₂SO₄ can sometimesaccelerate the epoxide opening reaction; (s3b-A5)—with the azide anionfrom sources such as but not limited to NaN₃ in alcoholic solvents suchas but not limited to ethanol or 1-propanol. Mild bases such as NaHCO₃or salts such as NH₄Cl or (NH₄)₂SO₄ can sometimes accelerate the epoxideopening reaction; and (s3b-A6)—with the cyanide anion from sources suchas but not limited to KCN in alcoholic solvents such as but not limitedto IPA or 1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Clor (NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction.

In the last step of the sequence, the final analogs of Formula (s3c-A1)through (s3c-A6) can be prepared by reacting the respective (s3b-A#)analogs with urea forming reagents such as but not limited toisocyanates; activated carbamoyl-chlorides, -imidazoles, —N— methylimidazoles; p-NO₂ phenol esters, and the like in aprotic solvents suchas DCM and mild bases such as but not limited to TEA or DIPEA.

Alternatively, the ureas can be prepared according to Scheme 4a. This4-step synthesis starts with the commercially availablebenzyloxycarbonyl (Cbz) protected tulathromycin epoxide. In the firststep, the dimethylamine moiety on the desosamine sugar is demethylatedusing Polonovski type conditions defined herein. In the second step, thesecondary methyl amine is activated with phosgene in the presence of amild base such as lutidine and quenched in situ with the desired aminesto form the urea functional group. In the subsequent step, the epoxidemoiety is opened with various nucleophiles such as but not limited toprimary and secondary amines, alcohols, thiols, cyanide, azide orhalogen anions and others at higher temperature in alcoholic solventssuch as but not limited to 1-propanol, 1-butanol or 2-propanol. Thisreaction can be completed overnight. Mild bases such as NaHCO₃ or saltssuch as NH₄Cl or (NH₄)₂SO₄ can sometimes accelerate the epoxide openingreaction. The details of this third step are presented in the scheme 4bbelow. The final analogs are revealed by removing the Cbz protectinggroup under catalytic Pd/C mediated hydrogenolysis with H₂ gas in analcoholic solvent such as ethanol, methanol, or trifluoroethanol. Thedetails of this last step are shown in the Scheme 4c below.

OCbz urea epoxide can be reacted to give the following compounds withFormula: (s4b-A1)—with various primary or secondary amines in alcoholicsolvents such as but not limited to methanol, ethanol or 1-propanol;(s4b-A2)—with various alcohols used as solvent such as but not limitedto methanol, ethanol or 1-propanol. Mild bases such as NaHCO₃ or saltssuch as NH₄Cl or (NH₄)₂SO₄ can sometimes accelerate the epoxide openingreaction; (s4b-A3)—with various thiols such as but not limited toethanethiol, propanethiol, isopropyl mercaptan and others in alcoholicsolvents such as but not limited to ethanol or 1-propanol. Mild basessuch as but not limited to NaHCO₃are used to accelerate the epoxideopening reaction; (s4b-A4)—with halides from reagents such as but notlimited to CeCl₃ or Br₂ in alcoholic solvents such as but not limited toethanol or 1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Clor (NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction;(s4b-A5)—with the azide anion from sources such as but not limited toNaN₃ in alcoholic solvents such as but not limited to ethanol or1-propanol. Mild bases such as NaHCO₃ or salts such as NH₄Cl or(NH₄)₂SO₄ can sometimes accelerate the epoxide opening reaction; and(s4b-A6)—with the cyanide anion from sources such as but not limited toKCN in alcoholic solvents such as but not limited to IPA or 1-propanol.Mild bases such as NaHCO₃ or salts such as NH₄Cl or (NH₄)₂SO₄ cansometimes accelerate the epoxide opening reaction.

In the last step of the sequence, the final analogs of Formula (s4c-A1)through (s4c-A6) can be prepared by deprotecting the Cbz protectinggroups on the respective (s4b-A#) analogs under hydrogenation conditionswith catalytic amounts of Pd/C in alcoholic solvents.

The alkyl-tula-epx intermediate can be easily synthesized from tulaepoxide (tula-epx) by a variety of methods such as but not limited toreductive aminations with the corresponding aldehyde and a hydridesource such as but not limited to STAB or NaBH₃CN in solvents such asalcohols or DMF and temperatures between 0° C. and 60° C. Subsequentchemistry to make compounds of the invention wherein the macrolide corenitrogen is alkylated with various R^(c) groups can be accomplished withSchemes 1-3, e.g., a Polonovski type demethylation, epoxide opening andurea formation by replacing the starting material Tula-epoxide in allSchemes 1-3 by R^(c)alkylated tulathromycin epoxide intermediate(alkyl-tula-epx); e.g., wherein R^(c) is propyl.

The (M8-epx) intermediate can be easily synthesized from M9 epoxide by avariety of methods such as a second demethylation with 12 and NaOMe or atriple sequence where M9 epoxide is first protected with a 4-OMe benzylgroup and then demethylated using a Polonovski demethylation. M8 epoxideis revealed by removing the protecting group under hydrogenolysisconditions using Pd/C and H₂ gas in alcoholic solvents such as but notlimited to methanol, ethanol or trifluoroethanol. M8 epoxide can be usedin various ways to prepare compounds of the invention as shown in theScheme 7 below.

M8 epoxide can be reacted with urea forming reagents such as but notlimited to isocyanates; activated carbamoyl-chlorides, -imidazoles,—N-methyl imidazoles; p-NO₂ phenol esters, and the like in aproticsolvents such as DCM and mild bases such as but not limited to TEA orDIPEA as shown on Scheme 7 to give compounds of the invention (s7′-A1)through (s7′-A6) after the opening of the epoxide. This chemistry is anadaptation of the chemistries described in Schemes 1-3.

M8 epoxide can also undergo a reductive amination with the correspondingR¹ aldehyde and a hydride source such as but not limited to STAB orNaBH₃CN in solvents such as alcohols, DMF, DCM or DCE and temperaturesbetween 0° C. and 60° C. Subsequent chemistry to make compounds of theinvention wherein R¹ is not CH₃ as in the tulathromycin derived analogscan be accomplished by adapting the chemistry from schemes 1-3 shownherein, to form the urea on the desosamine Nitrogen and open thecladinose epoxide with various nucleophiles. The urea functional groupcan be installed by using different urea forming reagents such as butnot limited to isocyanates; activated carbamoyl-chlorides, -imidazoles,—N-methyl imidazoles; p-NO₂ phenol esters, and the like in aproticsolvents such as DCM and mild bases such as but not limited to TEA orDIPEA whereas the epoxide can be opened up using different nucleophilessuch as primary and secondary amines, alcohols, thiols, cyanide, azideor halogen anions and others at higher temperature in alcoholic solventssuch as but not limited to 1-propanol, 1-butanol or 2-propanol as shownon Scheme 7 to give compounds of the invention (s7{circumflex over( )}-A1) through (s7{circumflex over ( )}-A6).

Azithromycin can be used as a starting material for the synthesis ofFormula (1) compounds of the invention as shown in Scheme 8.Azithromycin can undergo a demethylation reaction similar totulathromycin under similar conditions such as but not limited to thePolonovski reaction defined herein. Demethylated azithromycin can bereacted with urea forming reagents such as but not limited toisocyanates; activated carbamoyl-chlorides, -imidazoles, —N-methylimidazoles; p-NO₂ phenol esters, and the like in aprotic solvents suchas DCM and mild bases such as but not limited to TEA or DIPEA as shownon Scheme 8 to give compounds of the invention (s8′-A0). Moreover,des-methyl azithromycin can undergo a second demethylation as describedabove using I₂ and NaOMe followed by reductive amination with R¹corresponding aldehydes. Compounds of the invention (s8{circumflex over( )}-A0) can be synthesized by reacting the double demethylatedazithromycin with urea forming reagents such as but not limited toisocyanates; activated carbamoyl-chlorides, -imidazoles, —N-methylimidazoles; p-NO₂ phenol esters, and the like in aprotic solvents suchas DCM and mild bases such as but not limited to TEA or DIPEA as shownon Scheme 8.

Des-cladinose compounds of Formula (1.1) can be easily synthesized fromFormula (1A) compounds, by stirring said compound in aqueous acetic acidor hydrochloric acid at temperatures between 0° C. and 60° C. insolvents such as but not limited to THF, MeCN or H₂O for 1 to 72 hoursas shown in Scheme 9.

Des-cladinose urea compounds of Formula (1.1) can also be synthesizedaccording to the sequence shown in Scheme 10. Tulathromycin epoxide(tula epx) or N-core substituted Tula epoxide (alkyl tula epoxidesynthesized as shown in Scheme 5) can be demethylated according to thePolonovski demethylation conditions described herein. The cladinosesugar of des-methyl product can be cleaved off under aqueous acidicconditions with acids such as acetic or hydrochloric and others insolvents such as THE or acetonitrile. The urea functionality can beinstalled using urea forming reagents such as but not limited toisocyanates; activated carbamoyl-chlorides, -imidazoles, —N-methylimidazoles; p-NO₂ phenol esters, and the like in aprotic solvents suchas DCM and mild bases such as but not limited to TEA or DIPEA as shownon Scheme 10 to give the desired des-cladinose urea compounds of theinvention (s10-1.1).

EXAMPLES

Preparation of des-cladinose Example A-13 of Formula (1.1).

To crude example H-11 (600.0 mg) was added 2N HCl (10.0 mL) and theresulting mixture was heated at 45° C. for 2 hours before being cooledto room temperature. The crude reaction mixture was poured into an icecooled solution of NH₄OH (pH>7), stirred for 5 minutes, thenconcentrated and lyophilized. The crude material was purified by PrepHPLC using ammonium acetate as a buffer and the purified material waspassed through an SCX column to afford the product as the free base.

Formula (1.1) compounds can be made similarly to that shown above forExample A-13 under similar conditions but for the Formula (1-A1)starting materials.

Preparation of Example B-6 of Formula (1-A0); that is an application ofScheme 8.

Step 1: To a 500 mL round bottom flask was added azithromycin (20 g,26.77 mmol, 1 eq) in MeCOH (40 mL) and glacial acetic acid (3.4 mL,53.54 mmol, 2.2 eq), hexafluoroacetone (1.9 mL, 13.38 mmol, 0.5 eq) andH₂O₂ (30% w/w in H₂O, 5 mL) sequentially at 0° C. under a N₂ atmosphere.The reaction mixture was stirred at RT (25° C.) for 16 h beforeanhydrous CuSO₄ (6.4 g, 40.15 mmol, 1.5 eq) was added. The round bottomwas equipped with a reflux condenser and the reaction mixture wasstirred at 80° C. for 6 h under N₂ atmosphere. The reaction mixture wasthen cooled to room temperature, concentrated to remove MeCOH anddiluted with DCM (300 mL). The solution was filtered through celite andthe filtrate was basified to pH 10 using aqueous ammonia solution. Theorganic phase was separated, washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated to obtain the crude material. Thecrude material was triturated with pentane-diethyl ether (2:1) solutionto obtain the desired demethylated azithromycin as an off-white solid(13 g, 66.2%).

Step 2: To a stirred solution of des-methyl azithromycin (300 mg, 0.408mmol, 1 eq) in dry DCM (5 mL) was addedN-methyl-N-[4-(trifluoromethyl)phenyl]carbamoyl chloride (107 mg, 0.449mmol, 1.1 eq) and Et₃N (0.083 mL, 0.82 mmol, 2 eq) at RT. The reactionmixture was stirred at RT for 12 hours after which the LCMS analysisshowed full conversion of the starting material. The mixture wasconcentrated under reduced pressure, and the crude was purified on C₁₈silica using reverse flash chromatography with 1.0% AcOH as the modifier(0 to 100% MeCN in H₂O). The desired fractions were lyophilized to givethe desired urea product as a white solid acetate salt (260 mg, 64%).

Formula (1-A0) compounds can be made similarly to that shown above (B-6)under similar conditions by either varying the urea forming reagent orthe starting material and using tulathromycin epoxide instead ofazithromycin.

Preparation of Example C-1 of Formula (1-A2):

Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) andacetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3mmol) and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) weremixed together and stirred for 4 hours at 35° C. After consumption ofthe starting material as judged by LCMS, the reaction was cooled to 20°C. and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and thereaction was heated to 60° C. for 1 hour. After completion of thereaction as judged by LCMS, the reaction mixture was cooled to 20° C.and 60 mL DCM and 80 mL H₂O were added. The mixture was basified toapproximately pH 9.8 with concentrated aqueous ammonia. The mixture wasconcentrated under vacuum to a solid and recrystallized fromacetone/water to give 60 g of a white crystalline product (M9-epx) thatwas 95% pure by LCMS and used as is in the next step.

Step 2: M9 epoxide (M9-epx; 1.00 g, 1.36 mmol, 1.0 eq) was dissolved in10 mL dry EtOH in a pressure MW vial. The resulting solution was heatedto 120° C. in a microwave reactor for 12 hours. The volatiles were thenremoved under reduced pressure and the crude was purified on C₁₈ silicausing reverse flash chromatography with 1.0% AcOH as the modifier (0 to100% MeCN in H₂O The fractions containing the desired product werecombined, the pH was adjusted to pH˜12 with NH₄OH and extracted 3 timeswith 50 mL DCM to give the desired product as a free base (220 mg, 20%).

Step 3: The product from Step 2 (0.14 mmol, 110 mg, 1.00 eq) wasdissolved in DCM (5 ml) and cooled to −78° C. followed by the addictionof phenyl isocyanate (1.0 eq, 16 uL, 0.14 mmol) and the reaction wasleft to warm up to RT under stirring over 60 minutes. After completionof the reaction as judged by LCMS analysis, the volatiles were removedunder a stream of N₂ and the crude purified by C₁₈ reverse flashchromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H₂O). Thefractions containing the desired product were lyophilized to give thedesired product as the acetate salt (15 mg, 11%).

Preparation of Example D-2 of Formula (1-A3)

Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) andacetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3mmol) and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) weremixed together and stirred for 4 hours at 35° C. After consumption ofthe starting material as judged by LCMS, the reaction was cooled to 20°C. and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and thereaction was heated to 60° C. for 1 hour. After completion of thereaction as judged by LCMS, the reaction mixture was cooled to 20° C.and 60 mL DCM and 80 mL H₂O were added. The mixture was basified toapproximately pH 9.8 with concentrated aqueous ammonia. The mixture wasconcentrated under vacuum to a solid and recrystallized fromacetone/water to give 60 g of a white crystalline product (M9-epx) thatwas 95% pure by LCMS and used as is in the next step.

Step 2: M9 epoxide (M9-epx 1.00 g, 1.36 mmol, 1.0 eq) was dissolved in10 mL dry 1-propanol in a 25 mL round bottom flask. Potassiumbicarbonate (3.0 eq, 4.1 mmol, 410 mg) was added followed by1-propanethiol (5.0 eq, 6.8 mmol, 640 ul) and the resulting solution washeated to 50° C. overnight after which the LCMS analysis showedconsumption of the starting material. The reaction mixture was dilutedwith 20 mL DCM and H₂O and the pH was adjusted to pH˜12 with NH₄OH andextracted 3 times with 30 mL DCM to give the desired product as a freebase (1053 mg, 95%) and used as is in the following step.

Step 3: The product from Step 2 (0.25 mmol, 200 mg, 1.0 eq) wasdissolved in DCM (5 ml) and TEA (2.0 eq, 70 μL, 0.49 mmol) followed byN-methyl-N-phenyl-carbamoyl chloride (1.0 eq, 42 mg, 0.25 mmol) wereadded and the resulting solution was stirred at RT overnight. Aftercompletion of the reaction as judged by LCMS analysis, the volatileswere removed under a stream of N₂ and the crude purified by C₁₈ reverseflash chromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H₂O).The fractions containing the desired product were lyophilized to givethe desired product as the acetate salt (135 mg, 55%).

Preparation of Example E-3 of Formula (1-A4):

Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) andacetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3mmol) and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) weremixed together and stirred for 4 hours at 35° C. After consumption ofthe starting material as judged by LCMS, the reaction was cooled to 20°C. and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and thereaction was heated to 60° C. for 1 hour. After completion of thereaction as judged by LCMS, the reaction mixture was cooled to 20° C.and 60 mL DCM and 80 mL H₂O were added. The mixture was basified toapproximately pH 9.8 with concentrated aqueous ammonia. The mixture wasconcentrated under vacuum to a solid and recrystallized fromacetone/water to give 60 g of a white crystalline product (M9-epx) thatwas 95% pure by LCMS and used as is in the next step.

Step 2: M9 epoxide (M9-epx 5.00 g, 6.82 mmol, 1.0 eq) was dissolved in100 mL dry 1-propanol in a 250 mL round bottom flask. Ammonium chloride(3.0 eq, 20.5 mmol, 1.1 g) was added followed by cerium chloride (3.0eq, 20.5 mmol, 5.1 g) and the resulting solution was heated to 70° C.overnight after which the LCMS analysis showed consumption of thestarting material. The reaction mixture was diluted with 100 mL DCM andH₂O and the pH was adjusted to pH˜12 with NH₄OH and extracted 3 timeswith 100 mL DCM to give the desired product as a free base (5091 mg,97%) and used as is in the following step.

Step 3: The product from Step 2 (0.26 mmol, 200 mg, 1.0 eq) wasdissolved in DCM (5 ml) and TEA (2.0 eq, 73 μL, 0.52 mmol) followed byN-methyl-N-[4-(trifluoromethyl)phenyl]carbamoyl chloride (1.0 eq, 62 mg,0.26 mmol) were added and the resulting solution was stirred at RTovernight. After completion of the reaction as judged by LCMS analysis,the volatiles were removed under a stream of N₂ and the crude purifiedby C₁₈ reverse flash chromatography with 0.5% AcOH as modifier (0 to100% MeCN in H₂O). The fractions containing the desired product werelyophilized to give the desired product as the acetate salt (119 mg,44%)

Preparation of Example F-2 of Formula (1-A5):

Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) andacetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3mmol) and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) weremixed together and stirred for 4 hours at 35° C. After consumption ofthe starting material as judged by LCMS, the reaction was cooled to 20°C. and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and thereaction was heated to 60° C. for 1 hour. After completion of thereaction as judged by LCMS, the reaction mixture was cooled to 20° C.and 60 mL DCM and 80 mL H₂O were added. The mixture was basified toapproximately pH 9.8 with concentrated aqueous ammonia. The mixture wasconcentrated under vacuum to a solid and recrystallized fromacetone/water to give 60 g of a white crystalline product (M9-epx) thatwas 95% pure by LCMS and used as is in the next step.

Step 2: M9 epoxide (M9-epx 6.00 g, 8.19 mmol, 1.0 eq) was dissolved in100 mL dry 1-propanol in a 250 mL round bottom flask. Ammonium chloride(3.0 eq, 24.6 mmol, 1.31 g) was added followed by sodium azide (3.0 eq,24.6 mmol, 1.6 g) and the resulting solution was heated to 80° C.overnight after which the LCMS analysis showed consumption of thestarting material. The reaction mixture was diluted with 100 mL DCM andH₂O and the pH was adjusted to pH˜12 with NH₄OH and extracted 3 timeswith 100 mL DCM to give the desired product as a free base (5981 mg,94%) and used as is in the following step.

Step 3: The product from Step 2 (0.36 mmol, 282 mg, 1.0 eq) wasdissolved in DCM (5 ml) and TEA (2.0 eq, 102 μL, 0.73 mmol) followed byN-methyl-N-phenyl-carbamoyl chloride (1.0 eq, 62 mg, 0.36 mmol) wereadded and the resulting solution was stirred at RT overnight. Aftercompletion of the reaction as judged by LCMS analysis, the volatileswere removed under a stream of N₂ and the crude purified by C₁₈ reverseflash chromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H₂O).The fractions containing the desired product were lyophilized to givethe desired product as the acetate salt (180 mg, 51%).

Preparation of Example G-3 of Formula (1-A6):

Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) andacetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3mmol) and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) weremixed together and stirred for 4 hours at 35° C. After consumption ofthe starting material as judged by LCMS, the reaction was cooled to 20°C. and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and thereaction was heated to 60° C. for 1 hour. After completion of thereaction as judged by LCMS, the reaction mixture was cooled to 20° C.and 60 mL DCM and 80 mL H₂O were added. The mixture was basified toapproximately pH 9.8 with concentrated aqueous ammonia. The mixture wasconcentrated under vacuum to a solid and recrystallized fromacetone/water to give 60 g of a white crystalline product (M9-epx) thatwas 95% pure by LCMS and used as is in the next step.

Step 2: M9 epoxide (M9-epx 3.00 g, 4.09 mmol, 1.0 eq) was dissolved in50 mL dry 2-propanol in a 100 mL round bottom flask. Ammonium sulfate(3.0 eq, 12.3 mmol, 1.6 g) was added followed by potassium cyanide (6.0eq, 24.6 mmol, 1.6 g) and the resulting solution was heated to 80° C.for 48 hours after which the LCMS analysis showed consumption of thestarting material. The reaction mixture was diluted with 100 mL DCM andH₂O and the pH was adjusted to pH˜12 with NH₄OH and extracted 3 timeswith 30 mL DCM to give the desired product as a free base (2922 mg, 94%)and used as is in the following step.

Step 3: The product from Step 2 (0.13 mmol, 100 mg, 1.0 eq) wasdissolved in DCM (5 ml) and TEA (2.0 eq, 37 μL, 0.26 mmol) followed byN-methyl-N-phenyl-carbamoyl chloride (1.0 eq, 22 mg, 0.13 mmol) wereadded and the resulting solution was stirred at RT overnight. Aftercompletion of the reaction as judged by LCMS analysis, the volatileswere removed under a stream of N₂ and the crude purified by C₁₈ reverseflash chromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H₂O).The fractions containing the desired product were lyophilized to givethe desired product as the acetate salt (58 mg, 46%).

Formula (1-A2 through 1-A6) compounds can be made similarly to thatshown above (Examples C-1, D-2, E-3, F-2 and G-3) under similarconditions by either varying the urea forming reagent or the startingmaterial and using (alkyl-tula-epx) as the starting material instead oftulathromycin epoxide as shown in Scheme 5.

Preparation of Example H-11 of Formula (1-A1):

Step 1: To a solution of tulathromycin (tula) (20.0 g, 24.8 mmol) inmethanol (40 mL) and acetic acid (1.6 mL, 28 mmol), hexafluoroacetonetrihydrate (0.62 g, 2.8 mmol) and then 30% aqueous hydrogen peroxide(2.88 ml, 28 mmol) were added together and stirred for 4 hours at 35° C.After consumption of the starting material as judged by LCMS, thereaction was cooled to 20° C. and anhydrous copper(II) sulfate (4.35 g,28 mmol) was added and the reaction was heated to 60° C. for 2 hours.After completion of the reaction as judged by LCMS, the reaction mixturewas cooled to 20° C. and 60 mL DCM and 80 mL H₂O were added. The mixturewas basified to approximately pH 9.8 with concentrated aqueous ammonia.The mixture was concentrated under vacuum to a solid and recrystallizedfrom acetone/water to give 14.2 g of a white crystalline product(M9-epx) that was >95% pure by LCMS and used as is in the next step.

Step 2: M9 from Step 1 (0.25 mmol, 200 mg, 1.0 eq) was dissolved in DCM(5 ml) and TEA (2.0 eq, 70 uL, 0.49 mmol) followed by(N-methyl-N-phenyl-carbamoyl chloride (1.0 eq, 42 mg, 0.25 mmol) wereadded and the resulting solution was stirred at RT overnight. Aftercompletion of the reaction as judged by LCMS analysis, the volatileswere removed under a stream of N₂ and the crude purified by C₁₈ reverseflash chromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H₂O).The fractions containing the desired product were lyophilized to givethe desired product as the acetate salt (175 mg, 71%).

Formula (1-A1; Table H) and Formula (1-A1a; Table 1) compounds whereinR⁵ is H and R⁶ is propyl can be made similarly to that shown above forExample (H-11) under similar conditions by either varying the ureaforming reagent or the starting material and using (alkyl-tula-epx) asthe starting material instead of tulathromycin epoxide as shown inScheme 5. The following (1-A1) compounds follow the procedure of Example(H-11) and only the last, urea forming step is shown.

Preparation of Example H-8. To a solution of M9 (200 mg, 0.2525 mmol) inDCM (3 mL, 46.80 mmol) was added isocyanato(trimethyl)silane (1.5equiv., 0.3788 mmol) and the reaction was stirred at room temperaturefor 16 hours. The reactants were evaporated, MeCOH (10 mL) was added andthen evaporated. The residue was purified by prep HPLC to give a whitesolid as a TFA salt (79 mg).

Preparation of Example H-72: To a dry round bottom flask, M9 (400 mg,0.505 mmol) and 3-aminopyridine (47.53 mg, 0.505 mmol) were added to DCM(5 mL). The reaction mixture was cooled to −78° C. and triphosgene(44.962 mg, 0.152 mmol) was added followed 10 minutes later bytriethylamine (0.141 ml, 1.01 mmol). The mixture was stirred at −78° C.for 1 hour. The mixture was then concentrated and purified by Prep HPLCusing ammonium acetate as a buffer. Like fractions were combined,concentrated, and lyophilized. The lyophilized material was passedthrough an SCX/PL-HCO₃ resin column to make the free base. The free basewas then dissolved in 1 N AcOH solution, stirred for 30 minutes at roomtemperature, concentrated, and dissolved in t-BuOH and lyophilized toprovide the product as an acetate salt.

Preparation of Example H-91: To a solution of M9 (21.0 gm, 27 mmol) inmethylene chloride (200 mL) at 0° C. was slowly added phenylisocyanate(3.76 gm, 31.6 mmol). After 15 minutes, a solution of acetic acid (3.19gm, 53.0 mmol) in water (200 mL) was added and the product was extractedinto the aqueous layer. The organics were discarded. To the aqueoussolution was added methyl tert-butyl ether (175 mL) and the aqueouslayer was basified to pH 7.9 with 2N aqueous sodium hydroxide. Theproduct-containing organic layer was concentrated to a solid. The solidswere dissolved in methyl tert-butyl ether (80 mL) at 55° C. and aceticacid (1.7 gm, 28 mmol) was added. The resulting slurry was cooled to 5°C. and the product acetate salt was isolated by filtration. The solidswere dried under vacuum to afford 11.0 g of a white solid.

Preparation of Example I-4. To a solution of M9 (500 mg, 0.63 mmol) andTEA (114 μL, 1.3 equiv., 0.82 mmol) in DCM (5 mL) was addedindoline-1-carbonyl chloride (126 mg, 0.69 mmol) and4-dimethylaminopyridine (4 mg, 0.05 eq., 0.032 mmol). The mixture wasstirred at room temperature for 3 hours. The mixture was quenched withNaHCO₃ (sat. aq. soln.), separated, and the solvent was evaporated. Thecrude mixture was purified by Prep SFC (2PIC column) 25% MeCOH with NH₃to give a white solid.

Preparation of Example I-6: A solution of3,4-dihydro-2H-1λ6,4-benzothiazine 1,1-dioxide (183 mg, 0.99874 mmol)and pyridine (2 equiv. 1.9975 mmol) in DCM (5 mL, 78.00 mmol) was addeddropwise to a solution of triphosgene (0.4 equiv., 0.39950 mmol) in DCM(5 mL, 78.00 mmol) at −20° C. under N₂. The reaction mixture was allowedto warm to room temperature over 30 minutes and then stirred for 2 hoursat room temperature. The reaction was quenched with a 2M aqueoussolution of hydrogen chloride, separated and added to a solution of M9(700 mg, 0.8838 mmol) and TEA (1.3 equiv., 1.149 mmol) and4-dimethylaminopyridine (0.05 equiv., 0.04419 mmol) in DCM (5 mL, 78.00mmol). The mixture was stirred at room temperature overnight. Themixture was quenched with NaHCO₃ (sat. aq. soln.), separated, and thesolvent was evaporated. The crude mixture was purified by prep SFC (BiPcolumn, eluting with 26% MeCOH with NH₃ (aq) to give a white solid.

Preparation of Example H-27 of Formula (1-A1)

Step 1: A solution of(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one(tula-epx) (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol) and then30% aqueous hydrogen peroxide (0.62 g, 30 mmol) were mixed together andstirred for 4 hours at 35° C. After consumption of the starting materialas judged by LCMS, the reaction was cooled to 20° C. and anhydrouscopper(II) sulfate (4.5 g, 29 mmol) was added and the reaction washeated to 60° C. for 1 hour. After completion of the reaction as judgedby LCMS, the reaction mixture was cooled to 20° C. and 60 mL DCM and 80mL H₂O were added. The mixture was basified to approximately pH 9.8 withconcentrated aqueous ammonia. The mixture was concentrated under vacuumto a solid and recrystallized from acetone/water to give 60 g of a whitecrystalline product (M9-epx) that was 95% pure by LCMS and used as is inthe next step.

Step 2: A solution of 10 g (13.14 mmol) M9-epx from Step 1 and 9.12 mLcyclopropylamine (10.0 eq, 131.4 mmol) in 100 mL 1-propanol was heatedto 80° C. for 16 hours. After completion of the reaction as judged byLCMS analysis, the volatiles were removed under reduced pressure, thendissolved in 100 ml DCM and H₂O and the pH was adjusted to ˜9.8 withNH₄OH. The aqueous layer was extracted 3 times with DCM and the organiclayers combined, dried over anhydrous magnesium sulfate. The volatileswere removed under reduced pressure to give the crude material that waspurified on C₁₈ silica using reverse flash chromatography with 1.0% AcOHas the modifier (0 to 100% MeCN in H₂O). The desired fractions werecombined, the pH adjusted to ˜9.8 with NH₄OH and extracted 3 times withDCM. The organic layers were combined, dried over anhydrous magnesiumsulfate and the volatiles removed under reduced pressure to give thedesired material as an off-white amorphous solid (8.2 g).

Step 3: The product from Step 2 (0.39 mmol, 300 mg, 1.00 eq) wasdissolved in DCM (5 ml) followed by the addictionN-methyl-N-phenyl-carbamoyl chloride (1.0 eq, 63 mg, 0.39 mmol) and theresulting solution was stirred at RT overnight. After completion of thereaction as judged by LCMS analysis, the volatiles were removed under astream of N₂ and the crude purified by C₁₈ reverse flash chromatographywith 0.5% AcOH as modifier (0 to 100% MeCN in H₂O). The fractionscontaining the desired product were lyophilized to give the desiredcompound as the acetate salt (212 mg).

Formula (1-A1) and Formula (1-A1a) compounds shown in Tables H and I canbe made similarly to that shown above for Example (H-27) under similarconditions by either varying the amine used in the second step to openthe epoxide functional group or the urea forming reagent or the startingmaterial and using (alkyl-tula-epx) as the starting material instead oftulathromycin epoxide as shown in Scheme 5.

Preparation of Example J-7 of Formula (1-A1b):

Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) andacetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3mmol) and then 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) weremixed together and stirred for 4 hours at 35° C. After consumption ofthe starting material as judged by LCMS, the reaction was cooled to 20°C. and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and thereaction was heated to 60° C. for 1 hour. After completion of thereaction as judged by LCMS, the reaction mixture was cooled to 20° C.and 60 mL DCM and 80 mL H₂O were added. The mixture was basified toapproximately pH 9.8 with concentrated aqueous ammonia. The mixture wasconcentrated under vacuum to a solid and recrystallized fromacetone/water to give 60 g of a white crystalline product (M9-epx) thatwas 95% pure by LCMS and used as is in the next step.

Step 2: A solution of 10 g (13.14 mmol) M9-epx from Step 1 and 14.7 mL1-methylpiperazine (10.0 eq, 131.4 mmol) in 100 mL 1-propanol was heatedto 80° C. for 16 hours. After completion of the reaction as judged byLCMS analysis, the volatiles were removed under reduced pressure, thendissolved in 100 ml DCM and H₂O and the pH was adjusted to ˜9.8 withNH₄OH. The aqueous layer was extracted 3 times with DCM and the organiclayers combined, dried over anhydrous magnesium sulfate. The volatileswere removed under reduced pressure to give the crude material that waspurified on C₁₈ silica using reverse flash chromatography with 1.0% AcOHas the modifier (0 to 100% MeCN in H₂O). The desired fractions werecombined, the pH adjusted to ˜9.8 with NH₄OH and extracted 3 times withDCM. The organic layers were combined, dried over anhydrous magnesiumsulfate and the volatiles removed under reduced pressure to give thedesired material as an off-white amorphous solid.

Step 3: The product from Step 2 (0.390 mmol, 300 mg, 1.00 eq) wasdissolved in DCM (5 ml) and cooled to −78° C. followed by the addictionof phenyl isocyanate (1.0 eq, 44 uL mg) and the reaction was stirred for60 minutes while the temperature was slowly brought to room temperature.After completion of the reaction as judged by LCMS analysis, thevolatiles were removed under a stream of N₂ and the crude purified byC₁₈ reverse flash chromatography with 0.5% AcOH as modifier (0 to 100%MeCN in H₂O). The fractions containing the desired product werelyophilized to give the desired compound as the acetate salt (184 mg).

Formula (1-A1b) compounds shown in Table J can be made similarly to thatshown above for Example (J-7) under similar conditions by either varyingthe amine used in the second step to open the epoxide functional groupor the urea forming reagent or the starting material and using(alkyl-tula-epx) as the starting material instead of tulathromycinepoxide as shown in Scheme 5.

Example H-69 of Formula (1-A1) was prepared using a modification ofScheme 7 wherein the nucleophile used in the last step to open theepoxide is N-propylamine and such that R¹ is propyl from a reductiveamination reaction with propionaldehyde.

Step 1: 1.0 g (1.36 mmol, 1.00 eq) of M9 Epoxide was dissolved in 10 mLdry DMF in a 50 mL round bottom flask and 2.0 eq p-Anisaldehyde wasadded (0.332 mL, 2.73 mmol) followed by 1.17 g sodiumtriacetoxyborohydride (STAB, 4.0 eq, 5.5 mmol). The resulting solutionwas heated at 40° C. for 2 hours. An additional 0.6 g, (2.7 mmol, 2.0eq) STAB was added and the resulting solution was heated at 40° C.overnight after which the LCMS analysis showed full consumption of thestarting material. The reaction mixture was then cooled to 0° C. and 5mL of a saturated solution of NH₄Cl was added and the solution stirredfor 5 minutes. The reaction mixture was then diluted with DCM (30 mL andH₂O) and transferred to a separatory funnel. The pH was adjusted topH˜12 with NH₄OH and extracted 3 times with 20 mL DCM. The organics werecombined and dried over MgSO₄ and removed under reduced pressure toafford the crude material that was purified by reverse phasechromatography on a C18 column eluting with a gradient of 1% AcOH inMeCN and H₂O. The fractions containing the desired product werecombined, the pH was adjusted to pH˜12 with NH₄OH and extracted 3 timeswith 50 mL DCM to give the desired product as a free base (1008 mg,87%).

Step 2: 1008 mg of product from Step 1 (1.18 mmol, 1.00 eq) wasdissolved in 10 mL dry EtOH and peracetic acid was added (32% dilutesolution in acetic acid; 1.5 eq 304 ul). The resulting solution wasstirred at RT for 45 minutes after which the LCMS showed a fullconversion to the corresponding N-oxide. After that copper sulfate (II)anhydrous was added (3.0 eq; 566 mg) and the solution was stirred at 65°C. for 4 hours after which the LCMS showed a complete reaction with 41%debenzylated product and 44% demethylated product. The reaction mixturewas diluted with 20 mL DCM and H₂O and the pH adjusted to ˜12 withNH₄OH. The crude material was extracted 3 times with DCM and theorganics were combined, dried over MgSO₄ and the volatiles removed underreduced pressure. The crude was purified by reverse phase chromatographyon a C18 column with a gradient of 1% AcOH in MeCN and H₂O. Thefractions containing the desired product were combined, the pH wasadjusted to pH˜12 with NH₄OH and extracted 3 times with 50 mL DCM togive the desired product as a free base (250 mgs 25% yield)

Step 3: The product from Step 2 (250 mg, 0.30 mmol, 1.0 eq) wasdissolved in 10 mL CF₃CH₂OH. 5% Pd/C (25 mgs) was added and theresulting slurry was hydrogenated under balloon pressure H₂ at 40° C.overnight after which the LCMS showed complete reaction. The Pd/C wasfiltered off on Celite and the volatiles removed under reduced pressureto give the desired product (M8 epoxide; M8-epx) as a white powder (195mgs, 91%).

Step 4: The product from step 3 (M8-epx, 250 mgs, 1.0 eq, 0.35 mmol) wasdissolved in 5 mL dry MeCOH in a 25 mL round bottom flask and thesolution was cooled to 0° C. Propionaldehyde (1.2 eq, 30 ul) was addedfollowed by a portion wise addition of sodium triacetoxyborohydride (5eq, 369 mg). The solution was stirred at 0° C. to RT for 2 hours afterwhich the LCMS showed a full conversion to the desired product. Thereaction mixture was then cooled to 0° C. and 1 mL of a saturatedsolution of NH₄Cl was added and the solution stirred for 5 minutes. Thereaction mixture was then diluted with DCM (30 mL and H₂O) andtransferred to a separatory funnel. The pH was adjusted to pH˜12 withNH₄OH and extracted 3 times with 20 mL DCM. The organics were combinedand dried over MgSO₄ and removed under reduced pressure to afford thedesired product (250 mg) as a white solid material with ˜80% LCMS puritythat was used as is in subsequent epoxide opening.

Step 5: The material from Step 4 (200 mg, 0.32 mmol, 1.0 eq) wasdissolved in dry DCM (5 ml) in a dry round bottom flask and DIPEA (0.141mL, 2.5 eq.) was added followed by N-methyl-N-phenyl-carbamoyl chloride(66 mg, 1.2 eq, 0.39 mmol. The mixture was stirred overnight after whichthe LCMS analysis indicated all starting material being consumed. Thevolatiles were removed under a stream of N₂ and the crude material waspurified by reverse phase chromatography on a C18 column with a gradientof 1% AcOH in MeCN and H₂O. The fractions containing the desired productwere combined, the pH was adjusted to pH˜12 with NH₄OH and extracted 3times with 50 mL DCM to give the desired product as a free base (93 mgs32% yield).

Step 6: To a pressure vial was added the product from step 2 (93 mg,0.10 mmol, 1 eq) and EtOH (2 mL) followed by N-propylamine (103 ul, 1.25mmol, 12 eq). The reaction mixture was stirred at 80° C. for 16 hours.The reaction mixture was then concentrated under vacuum and the crudeproduct was purified by reverse phase chromatography on a C18 columnwith a gradient of 1% AcOH in MeCN and H₂O. The fractions containing thedesired product were lyophilized to give the desired product as theacetate salt as a white solid (35 mg, 33% yield).

Following this example, the alkyl group R¹ on the desosamine nitrogencan be varied by replacing propionaldehyde in the fourth step of thesequence by any other alkyl aldehyde such as but not limited toacetaldehyde or isobutylaldehyde or carbaldehydes such as benzaldehyde,or 2-pyridyl carbaldehyde and others. Similarly to other examples shownherein, the epoxide can be opened with various nucleophiles such as butnot limited to primary and secondary amines, alcohols, thiols, cyanide,azide or halogen anions and others at higher temperature in alcoholicsolvents such as but not limited to 1-propanol, 1-butanol or 2-propanolin the last step.

Preparation of Example H-102 of Formula (1-A1) using a modification ofScheme 5 wherein the aldehyde used in the first step is propionaldehydeand the nucleophile used in the last step to open the epoxide is1-propylamine:

Step 1: To a solution of tula-epx (1.0 g, 1.34 mmol) in dry DMF (10 mL)was added STAB and the resulting solution was stirred for 4 hours at 35°C. After consumption of the starting material as judged by LCMS, thereaction was cooled to 0° C. and 2 mL of a saturated solution of NH₄Clwas added and the solution stirred for 5 minutes. The reaction mixturewas then diluted with DCM (30 mL and H₂O) and transferred to aseparatory funnel. The pH was adjusted to pH˜12 with NH₄OH and extracted3 times with 20 mL DCM. The organics were combined and dried over MgSO₄and removed under reduced pressure to afford the crude material that waspurified by reverse phase chromatography on a C18 column with a gradientof 1% AcOH in MeCN and H₂O. The fractions containing the desired productwere combined, the pH was adjusted to pH˜12 with NH₄OH and extracted 3times with 50 mL DCM to give the desired product as a free base (600mgs, 57% yield).

Step 2: 600 mg of product from step 1 (0.76 mmol, 1.00 eq) was dissolvedin 10 mL dry EtOH and peracetic acid was added (32% dilute solution inacetic acid; 1.2 eq 192 ul). The resulting solution was stirred at RTfor 45 minutes after which the LCMS showed a full conversion to thecorresponding N-oxide. The reaction mixture was then diluted with DCM(30 mL and H₂O) and transferred to a separatory funnel. The pH wasadjusted to pH˜12 with NH₄OH and extracted 3 times with 20 mL DCM. Theorganics were combined and dried over MgSO₄ and removed under reducedpressure to afford the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0eq) was dissolved in 10 mL dry ethanol and copper sulfate (II)pentahydrate was added (5.0 eq; 950 mg) and the solution was stirred at65° C. for 16 hours after which the LCMS showed a complete reaction. Thereaction mixture was diluted with 20 mL DCM and H₂O and the pH adjustedto ˜12 with NH₄OH. The crude material was extracted 3 times with DCM andthe organics were combined, dried over MgSO₄ and the volatiles removedunder reduced pressure to give the crude desired product with LCMSpurity >90% that was used as is in the following step.

Step 3: The material from Step 2 (250 mg, 0.32 mmol, 1.0 eq) wasdissolved in dry DCM (5 ml) in a dry round bottom flask and DIPEA (0.141mL, 2.5 eq.) was added followed by N-methyl-N-phenyl-carbamoyl chloride(66, 1.2 eq, 0.39 mmol). The reaction was stirred for 16 hrs at RT afterwhich the LCMS analysis indicated all starting material being consumed.The volatiles were removed under a stream of N₂ and the crude materialwas purified by reverse phase chromatography on a C18 column with agradient of 1% AcOH in MeCN and H₂O. The fractions containing thedesired product were combined, the pH was adjusted to pH˜12 with NH₄OHand extracted 3 times with 50 mL DCM to give the desired product as afree base (150 mgs 51% yield).

Step 4: To a pressure vial was added the product from step 3 (150 mg,0.17 mmol, 1 eq) and N-propanol (5 mL) followed by the additionN-propylamine (117 ul, 2.0 mmol, 12 eq). The reaction mixture wasstirred at 70° C. for 16 hours. The reaction mixture was thenconcentrated under vacuum and the crude product was purified by reversephase chromatography using a C18 column with a gradient of 1% AcOH inMeCN and H₂O. The fractions containing the desired product werelyophilized to give the desired product as an acetate salt (90 mg, 53%yield).

Following this example, the alkyl group R² on the core nitrogen can bevaried by replacing propionaldehyde in the first step of the sequence byany other alkyl aldehyde such as but not limited to formaldehyde oracetaldehyde and others. Similarly to other examples shown herein, theepoxide can be opened with various nucleophiles such as but not limitedto primary and secondary amines, alcohols, thiols, cyanide, azide orhalogen anions and others at higher temperature in alcoholic solventssuch as but not limited to 1-propanol, 1-butanol or 2-propanol in thelast step.

NMR data for the tabulated Examples are provided below each of therespective Example Tables/Names.

EXAMPLES

Formula (1) compounds were prepared in accordance with the Schemes andprocedures defined herein and that which is known in the art.

The following Formula (1.1) compounds were prepared as defined herein;wherein R⁰ is H and R¹ is methyl; are shown in Table A. The respectivecompound names are provided below the table.

TABLE A Formula (1.1) Compounds Ex # R² R³ Mass [M + H]⁺ A-1 H

685 A-2 H

685 A-3 H pyridin-2yl 684 A-4 H pyridin-3yl 684 A-5 H pyridin-4yl 684A-6 H

687 A-7 H

701 A-8 H 2-methoxyphenyl 712 A-9 H 4-cyanophenyl 707 A-10 H3-trifluoromethylphenyl 750 A-11 H 3-cyanophenyl 707 A-12 H2-chlorophenyl 716 A-13 H phenyl 682 A-14 H 2-methylphenyl 696 A-15 H4-trifluoromethylphenyl 750 A-16 H 2-trifluoromethylphenyl 750 A-17 H2-fluorophenyl 700 A-18 H 4-fluorophenyl 700 A-19 H 4-chlorophenyl 716A-20 H 3-fluorophenyl 700 A-21 H 3-methoxyphenyl 712 A-22 H4-methoxyphenyl 712 A-23 H 3-chlorophenyl 716 A-24 H 4-methylphenyl 696A-25 H 3-methylphenyl 695 A-26 methyl phenyl 696

Table A Example Names:

A-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyrimidin-2-yl)urea;A-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyrazin-2-yl)urea;A-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-2-yl)urea;A-4.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-3-yl)urea;A-5.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-4-yl)urea;A-6.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)urea;A-7.3-(1,5-dimethyl-1H-pyrazol-3-yl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;A-8.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-methoxyphenyl)-1-methylurea;A-9.3-(4-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;A-10.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea;A-11.3-(3-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;A-12.3-(2-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;A-13.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;A-14.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(o-tolyl)urea;A-15.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea;A-16.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(2-(trifluoromethyl)phenyl)urea;A-17.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-fluorophenyl)-1-methylurea;A-18.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea;A-19.3-(4-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;A-20.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-fluorophenyl)-1-methylurea;A-21.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-methoxyphenyl)-1-methylurea;A-22.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-methoxyphenyl)-1-methylurea;A-23.3-(3-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;A-24.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(p-tolyl)urea;A-25.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(m-tolyl)urea;andA-26.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea.

TABLE A Example NMR's ¹H NMR (400 MHz, DMSO-d6) (unless describedotherwise) δ ppm A-1  0.5-1.5 (m, 31H), 1.5-2.3 (m, 4H), 2.4-3.0 (m,6H), 3.22 (t, 1H), 3.31-3.34 (m, 2H), 3.47 (s, 1H), 3.52 (brs, 1H), 3.99(d, 1H), 4.09 (s, 1H), 4.24 (s, 1H), 4.67 (d, 1H), 4.96 (d, 1H), 5.20(brs, 2H), 7.00 (t, 1H), 8.52 (d, 2H), 9.14 (brs, 1H). A-2  0.5-1.5 (m,32H), 1.5-2.3 (m, 4H), 2.4-2.9 (m, 6H), 3.0 (brd, 1H), 3.47 (s, 1H),3.57 (brs, 1H), 4.09 (brs, 2H), 4.16 (brs, 2H), 4.68 (d, 1H), 4.97 (d,1H), 5.1 (brs, 2H), 8.18 (s, 1H), 8.27 (s, 1H), 9.01 (s, 1H), 9.17 (s,1H). A-3  0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.21 (brs,1H), 3.31 (brs, 1H), 3.47 (s, 1H), 3.56 (brs, 1H), 4.07 (br d, 2H), 4.24(d, 1H), 4.67 (d, 1H), 4.96 (d, 1H), 5.10 (brs, 1H), 5.20 (d, 1H), 6.94(t, 1H), 7.66 (t, 1H), 7.75 (d, 1H), 8.20 (s, 1H), 8.74 (s, 1H). A-4 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.24 (brt, 1H), 3.33(d, 1H), 3.38 (t, 1H), 3.51 (s, 1H), 3.56 (t, 1H), 4.13 (brs, 1H), 4.37(brs, 1H), 4.67 (d, 1H), 4.85 (d, 1H), 5.01 (d, 1H), 5.22 (d, 1H),7.23-7.26 (m, 1H), 7.86 (d, 1H), 8.13 (brs, 1H), 8.40 (s, 1H), 8.64 (s,1H). A-5  0.5-1.5 (m, 33H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.22 (t,1H), 3.32-3.38 (m, 1H), 3.46 (s, 1H), 3.56 (brs, 1H), 4.11 (brs, 2H),4.25 (brs, 1H), 4.66 (d, 1H), 4.96 (d, 1H), 5.25 (brs, 1H), 7.49 (d,2H), 8.28 (d, 2H), 8.68 (s, 1H). A-6  0.5-1.5 (m, 33H), 1.5-2.3 (m, 4H),2.4-3.0 (m, 6H), 3.21 (brs, 1H), 3.31 (brs, 1H), 3.49 (s, 1H), 3.56(brs, 1H), 3.73 (s, 3H), 4.08 (brs, 1H), 4.30 (brs, 1H), 4.64 (d, 1H),4.75 (d, 1H), 4.96 (d, 1H), 5.19 (d, 1H), 7.33 (s, 1H), 7.62 (s, 1H),8.20 (s, 1H). A-7  0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 9H),3.23 (brs, 1H), 3.31 (brs, 1H), 3.35-3.42 (m, 3H), 3.55 (s, 3H), 4.09(s, 1H), 4.24 (d, 1H), 4.63 (d, 1H), 4.85 (s, 1H), 4.96 (d, 1H), 5.19(d, 1H), 6.07 (s, 1H), 8.47 (s, 1H). A-8  0.5-1.5 (m, 32H), 1.5-2.3 (m,4H), 2.4-3.0 (m, 6H), 3.22 (brs, 1H), 3.32- 3.35 (m, 1H), 3.47 (s, 1H),3.55 (brs, 1H), 3.81 (s, 3H), 3.99 (brs, 1H), 4.10 (brs, 1H), 4.26 (brs,1H), 4.69 (d, 1H), 4.97 (d, 1H), 5.23 (brs, 2H), 6.82- 6.86 (m, 1H),6.89-6.97 (m, 2H), 7.79 (d, 1H), 7.87 (brs, 1H). A-9  0.5-1.5 (m, 32H),1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.24 (brs, 1H), 3.31 (brs, 1H), 3.46(s, 1H), 3.56 (br t, 1H), 4.09 (brs, 2H), 4.24 (d, 1H), 4.66 (d, 1H),4.89 (brs, 1H), 4.96 (d, 1H), 5.19 (d, 1H), 7.66 (s, 4H), 8.71 (s, 1H).A-10 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.22 (brs, 1H),3.32 (brs, 1H), 3.47 (s, 1H), 3.57 (brs, 1H), 4.12 (brs, 2H), 4.26 (brs,1H), 4.66 (d, 1H), 4.89 (brs, 1H), 4.96 (d, 1H), 5.23 (brs, 1H), 7.24(d, 1H), 7.44 (t, 1H), 7.74 (d, 1H), 7.93 (s, 1H), 8.59 (s, 1H). A-110.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.24 (d, 1H), 3.32(brs, 1H), 3.39 (s, 1H), 3.47 (brs, 1H), 4.11 (brs, 2H), 4.25 (d, 1H),4.66 (d, 1H), 4.87 (s, 1H), 4.96 (d, 1H), 5.20 (d, 1H), 7.35 (d, 1H),7.43 (t, 1H), 7.76 (d, 1H), 7.93 (s, 1H), 8.56 (s, 1H). A-12 0.5-1.5 (m,33H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 7H), 3.22 (brs, 1H), 3.32 (brs, 1H),3.47 (s, 1H), 3.54 (brs, 1H), 4.01 (brs, 1H), 4.10 (s, 1H), 4.25 (d,1H), 4.69 (d, 1H), 4.96 (d, 1H), 5.21 (d, 1H), 7.24 (t, 1H), 7.41 (d,1H), 7.68 (d, 1H), 8.02 (brs, 1H). A-13 0.5-1.5 (m, 32H), 1.5-2.3 (m,4H), 2.4-3.0 (m, 6H), 3.21 (brs, 1H), 3.46 (s, 1H), 3.6 (brs, 1H), 4.10(brs, 2H), 4.25 (d, 1H), 4.65 (d, 1H), 4.87 (brs, 1H), 4.96 (d, 1H),5.21 (d, 1H), 6.45 (brs, 1H), 6.92-6.90 (m, 1H), 7.21 (t, 2H), 7.44 (d,2H), 8.20 (s, 1H). A-14 0.5-1.5 (m, 31H), 1.5-2.3 (m, 4H), 2.4-3.0 (m,9H), 3.20-3.23 (m, 1H), 3.25-3.31 (m, 2H), 3.47 (s, 1H), 3.53-3.54 (m,1H), 4.06-4.08 (m, 2H), 4.26 (brs, 1H), 4.67 (d, 1H), 4.95 (d, 1H), 4.98(brs, 2H), 6.96 (t, 1H), 7.07-7.15 (m, 2H), 7.26 (d, 1H), 7.84 (s, 1H).A-15 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.31 (brs, 1H),3.47 (s, 2H), 3.56 (brs, 1H), 4.11 (brs, 2H), 4.25 (d, 1H), 4.66 (d,1H), 4.89 (brs, 1H), 4.96 (d, 1H), 4.20 (d, 1H), 7.57 (d, 2H), 7.68 (d,2H), 8.61 (s, 1H). A-16 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m,6H), 3.22 (brs, 1H), 3.32 (brs, 1H), 3.4 (s, 1H), 3.52 (brs, 1H), 4.0(brs, 1H), 4.10 (s, 1H), 4.26 (d, 1H), 4.66 (d, 1H), 4.97 (d, 1H), 5.19(d, 2H), 7.28 (t, 1H), 7.52-7.64 (m, 3H), 8.05 (s, 1H). A-17 0.5-1.5 (m,32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.24 (brs, 1H), 3.31 (brs, 1H),3.47 (s, 1H), 3.55 (br t, 1H), 4.06 (br d, 2H), 4.23 (d, 1H), 4.66 (d,1H), 4.96 (d, 1H), 5.06 (brs, 1H), 5.19 (d, 1H), 7.03-7.48 (m, 3H),7.50-7.52 (m, 1H), 8.07 (s, 1H). A-18 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H),2.4-3.0 (m, 6H), 3.22 (brs, 1H), 3.39 (brs, 1H), 3.50 (s, 1H), 3.6 (brs,2H), 4.1 (brs, 2H), 4.66 (d, 1H), 4.83 (d, 1H), 5.0 (d, 1H), 5.23 (d,1H), 7.05 (t, 2H), 7.43-7.46 (m, 2H), 8.24 (s, 1H). A-19 0.5-1.5 (m,32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.20 (brs, 1H), 3.31 (brs, 1H),3.47 (s, 1H), 3.55 (brs, 1H), 4.12 (brs, 2H), 4.26 (d, 1H), 4.65 (d,1H), 4.85 (s, 1H), 4.96 (d, 1H), 5.19 (d, 1H), 7.26 (d, 2H), 7.49 (d,2H), 8.3 (s, 1H). A-20 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m,6H), 3.21 (brs, 1H), 3.31- 3.35 (m, 1H), 3.47 (s, 1H), 3.56 (brs, 1H),4.1 (brs, 2H), 4.24 (d, 1H), 4.65 (d, 1H), 4.85 (brs, 1H), 4.96 (d, 1H),4.19 (d, 1H), 6.69-6.71 (m, 1H), 7.23 (d, 2H), 7.44 (d, 1H), 8.40 (s,1H). A-21 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H), 3.19 (brs,1H), 3.35 (brs, 1H), 3.36-3.38 (m, 1H), 3.51 (s, 1H), 3.58 (brs, 1H),3.68 (s, 3H), 4.11 (brs, 1H), 4.4 (brs, 1H), 4.66 (d, 1H), 4.85 (d, 1H),5.01 (d, 1H), 5.24 (d, 1H),), 6.49 (d, 1H), 7.03 (d, 1H), 7.08-7.12 (m,1H), 7.17 (s, 1H), 8.18 (s, 1H). A-22 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H),2.4-3.0 (m, 6H), 3.20 (brs, 1H), 3.32- 3.35 (m, 1H), 3.46 (s, 1H), 3.54(brs, 1H), 3.69 (s, 3H), 4.41 (brs, 2H), 4.25 (d, 1H), 4.64 (d, 1H),4.83 (brs, 1H), 4.96 (d, 1H), 5.20 (d, 1H), 6.80 (d, 2H), 7.32 (d, 2H),8.04 (s, 1H). A-23 0.5-1.5 (m, 30H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 6H),3.18-3.20 (m, 2H), 3.31 (d, 2H), 3.44 (t, 1H), 3.47 (brs, 2H), 4.10(brs, 1H), 4.50 (d, 1H), 4.67 (d, 1H), 4.85 (d, 1H), 4.94 (brs, 1H),5.03 (d, 1H), 5.26 (d, 1H), 7.23 (t, 1H), 7.41 (d, 1H), 7.63 (s, 1H),8.41 (s, 1H). A-24 0.5-1.5 (m, 32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 9H),3.22 (brs, 1H), 3.32 (brs, 1H), 3.46 (s, 1H), 3.55 (brs, 1H), 4.11 (brt, 2H), 4.28 (brs, 1H), 4.64 (d, 1H), 4.83 (d, 1H), 4.96 (d, 1H), 5.19(d, 1H), 7.01 (d, 2H), 7.32 (d, 2H), 8.09 (s, 1H). A-25 0.5-1.5 (m,32H), 1.5-2.3 (m, 4H), 2.4-3.0 (m, 9H), 3.18-3.21 (m, 1H), 3.31-3.35 (m,1H), 3.37 (s, 1H), 3.6 (brs, 1H), 4.11 (brs, 2H), 4.26 (d, 1H), 4.65 (d,1H), 4.84 (d, 1H), 4.96 (d, 1H), 5.19 (d, 1H), 6.73 (d, 1H), 7.06 (t,1H), 7.26-7.23 (m, 2H), 8.11 (s, 1H). A-26 METHANOL-d4) δ ppm 0.9-1.5(28H), 1.61 (m, 1H), 1.77 (d, 1H), 1.90 (m, 1H), 2.05 (br, 1H), 2.18 (q,1H), 2.51 (s, 3H), 2.63 (t, 1H), 2.75 (m, 1H), 3.20 (s, 3H), 3.29 (m,1H), 3.40 (m, 1H), 3.5-3.6 (mm, 2H), 3.63 (d, 1H), 3.74 (s, 1H), 4.03(dt, 1H), 4.72 (d, 1H), 4.98 (d, 1H), 7.15 (t, 1H), 7.24 (d, 2H), 7.37(t, 2H)

The following Formula (1-A0) compounds were prepared in accordance withthe Schemes and procedures defined herein, and wherein R¹ is methyl; areshown in Table B. The respective compound names are provided below thetable. Examples B-1a, B-2a, B-3a and B-13a are stereoisomers of B-1,B-2, B-3 and B-13, respectively, (i.e., hydroxyl diastereomers at theR^(a) alpha carbon (5R in lieu of 5S))

TABLE B Formula (1-A0) Compounds Mass Ex# R⁰ R^(a) R² R³ [M + H]⁺ B-1* Hmethyl methyl phenyl 869 B-1a H methyl methyl phenyl 869 B-2  H H methyl4-trifluoromethyl- 922 phenyl B-2a H H methyl 4-trifluoromethyl- 922phenyl B-3  H H methyl phenyl 854 B-3a H H methyl phenyl 854 B-4  methylH H phenyl 854 B-5  methyl H methyl phenyl 868 B-6  methyl H methyl4-trifluoromethyl- 936 phenyl B-7* methyl H H 4-dimethylamino- 897phenyl B-8  methyl H H 4-trifluoromethyl- 922 phenyl B-9  methyl H H4-fluorophenyl 872 B-10 methyl H H cyclohexyl 860 B-11 methyl H Ht-butyl 834 B-12 methyl H H 4-cyanophenyl 879 B-13 H methyl methyl4-trifluoromethyl- 936 phenyl  B-13a H methyl methyl 4-trifluoromethyl-936 phenyl B-14 propyl H methyl 4-trifluoromethyl- phenyl B-15 propyl Hmethyl phenyl *MIC ≤ 64 μg/mL for at least one BRD bacterial strain

Table B Example Names:

B-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;B-1a.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5R,6S)-5-hydroxy-4-methoxy-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11S-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;B-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;B-2a.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5R,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;B-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;B-3a.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5R,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;B-4.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;B-5.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;B-6.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;B-7.3-(4-(dimethylamino)phenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;B-8.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea;B-9.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea;B-10.3-cyclohexyl-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;B-11.3-(tert-butyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;B-12.3-(4-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;B-13.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;B-13a.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5R,6S)-5-hydroxy-4-methoxy-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;B-4.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,1R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea(964); andB-5.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,1R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(896).

TABLE B Example NMR's ¹H NMR: 400 MHz, DMSO-d6 (unless otherwisespecified) δ ppm B-1{circumflex over ( )} 0.74-1.18 (m, 32 H), 1.19 (brs, 6 H), 1.60-1.90 (m, 4 H), 1.90 (s, 1 H), 1.91-1.98 (m, 2 H), 2.43 (s,3 H), 2.60-2.71 (m, 2 H), 2.81-2.89 (m, 1 H), 2.90-3.00 (m, 1 H), 3.05(s, 3 H), 3.08-3.16 (m, 1 H), 3.31-3.33 (m, 5 H), 3.34 (br s, 1 H),3.37-3.45 (m, 1 H), 3.48 (br d, 1 H), 3.68- 3.80 (m, 1 H), 3.87 (td, 1H), 4.16 (br s, 1 H), 4.20 (s, 1 H), 4.22-4.29 (m, 1 H), 4.29-4.35 (m, 1H), 4.84 (dd, 1 H), 4.90 (t, 2 H), 7.05 (t, 1 H), 7.11- 7.18 (m, 2 H),7.25-7.33 (m, 2 H)  B-1a{circumflex over ( )} 0.72-1.20 (m, 32 H),1.20-1.86 (m, 9 H), 1.89 (s, 2 H), 1.92 (br d, 1 H), 2.20 (br d, 1 H),2.41-2.47 (m, 3 H), 2.52-2.59 (m, 1 H), 2.61-2.70 (m, 1 H), 2.79-2.86(m, 1 H), 3.02 (br d, 1 H), 3.05 (s, 3 H), 3.09-3.17 (m, 2 H), 3.36 (brs, 6 H), 3.38 (s, 3 H), 3.46 (br d, 1 H), 3.67-3.78 (m, 1 H), 3.81-3.90(m, 1 H), 4.13 (br s, 1 H), 4.30 (q, 1 H), 4.35 (br d, 1 H), 4.83 (brdd, 1 H), 4.89 (br d, 1 H), 7.06 (t, 1 H), 7.14 (d, 2 H), 7.27-7.33 (m,2 H) B-2{circumflex over ( )} 0.70-1.21 (m, 32 H), 1.22-1.88 (m, 11 H),1.90 (s, 1 H), 1.91-1.96 (m, 1 H), 2.27 (br d, 1 H), 2.52 (br s, 3 H),2.58 (br d, 1 H), 2.62-2.71 (m, 1 H), 2.85 (br d, 1 H), 2.94 (dd, 1 H),3.12 (s, 3 H), 3.14-3.21 (m, 1 H), 3.24 (s, 3 H), 3.53 (br d, 1 H), 3.77(br dd, 2 H), 3.95-4.05 (m, 1 H), 4.07- 4.11 (m, 1 H), 4.12 (br s, 1 H),4.27 (br d, 1 H), 4.45 (d, 1 H), 4.83 (dd, 1 H), 4.88 (d, 1 H), 5.02 (d,1 H), 7.30 (d, 2 H), 7.60 (d, 2 H)  B-2a{circumflex over ( )} 0.67-1.21(m, 32 H), 1.22-1.55 (m, 7 H), 1.57-1.86 (m, 4 H), 1.89 (s, 2 H), 1.91(br s, 1 H), 2.27 (br d, 1 H), 2.51 (br s, 3 H), 2.53-2.58 (m, 1 H),2.66 (dt, 1 H), 2.84 (br d, 1 H), 2.94 (br dd, 1 H), 3.12 (s, 3 H),3.14-3.20 (m, 1 H), 3.24 (s, 3 H), 3.53 (br d, 1 H), 3.72-3.82 (m, 2 H),3.95-4.04 (m, 1 H), 4.07-4.11 (m, 1 H), 4.12 (br s, 1 H), 4.28 (br d, 1H), 4.44 (br d, 1 H), 4.83 (br dd, 1 H), 4.88 (br d, 1 H), 5.03 (d, 1H), 7.30 (br d, 2 H), 7.60 (br d, 2 H) B-3{circumflex over ( )}0.70-1.20 (m, 32 H), 1.21-1.84 (m, 12 H), 1.89 (br s, 2 H), 2.28 (br dd,1 H), 2.41 (br d, 3 H), 2.54 (br d, 2 H), 2.65 (br d, 1 H), 2.83 (br dd,1 H), 2.91-2.97 (m, 1 H), 3.04 (br d, 3 H), 3.07-3.17 (m, 2 H), 3.50 (brs, 1 H), 3.62-3.70 (m, 1 H), 3.77 (br s, 1 H), 3.88-3.98 (m, 1 H),4.03-4.16 (m, 3 H), 4.20-4.31 (m, 1 H), 4.38-4.45 (m, 1 H), 4.75-4.85(m, 2 H), 4.88 (br s, 1 H), 7.00-7.08 (m, 1 H), 7.11-7.21 (m, 2 H), 7.30(br d, 2 H)  B-3a{circumflex over ( )} ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.72-1.27 (m, 32 H), 1.27-1.88 (m, 10 H), 1.91 (br s, 2 H, AcOH), 1.98(br s, 1 H), 2.25-2.35 (m, 1 H), 2.42 (br d, 3 H), 2.53-2.60 (m, 2 H),2.67 (br s, 1 H), 2.84 (br dd, 1 H), 2.92-3.01 (m, 1 H), 3.06 (br d, 3H), 3.10-3.16 (m, 1 H), 3.31 (br s, 3 H), 3.51 (br d, 1 H), 3.62-3.72(m, 1 H), 3.76-3.86 (m, 1 H), 3.93 (br dd, 1 H), 4.05-4.21 (m, 3 H),4.43 (br d, 1 H), 4.83 (br d, 2 H), 4.89 (br s, 1 H), 7.01-7.10(m, 1 H),7.16 (br d, 2 H), 7.31 (br d, 2 H) B-4 CHLOROFORM-d 0.78-1.05 (m, 14H),1.12-1.27 (m, 16H), 1.36-2.03 (m, 14H), 2.18-2.35 (m, 5H), 2.43-2.52 (m,1H), 2.54-2.89 (m, 1H), 2.74-2.82 (m, 1H), 2.85 (s, 1H), 2.81-2.89 (m,1H), 2.91-3.04 (m, 1H), 3.25 (s, 3H), 3.32-3.42 (m, 1H), 3.53-3.64 (m,3H), 3.93-4.06 (m, 1H), 4.08-4.22 (m, 2H), 4.13-4.21 (m, 2H), 4.42-4.52(m, 1H), 4.57-4.68 (m, 1H), 4.96-5.05 (m, 1H), 6.93 (s, 1H), 7.18-7.25(m, 4H) B-5 0.5-1.5 (m, 37H), 1.5-2.3 (m, 10H), 2.4-3.0 (m, 6H), 3.04(s, 3H), 3.11 (brs, 1H), 3.29 (s, 3H), 3.47 (br d, 2H), 3.66 (brs, 1H),3.93 (brs, 1H), 4.08 (br t, 1H), 4.16 (d, 2H), 4.29 (brs, 1H), 4.42 (d,1H), 4.75 (brs, 1H), 4.84 (brs, 2H), 7.04 (t, 1H), 7.15 (d, 2H), 7.30(t, 2H). B-6{circumflex over ( )} 0.5-1.5 (m, 37H), 1.5-2.3 (m, 13H),2.4-3.0 (m, 6H), 3.11 (s, 3H), 3.2 (brs, 1H), 3.3 (s, 3H), 3.44 (d, 1H),3.52 (d, 1H), 4.08 (brs, 1H), 4.14 (br t, 1H), 4.31 (brs, 1H), 4.45 (d,3H), 4.72 (d, 1H), 4.74 (d, 1H), 4.84 (d, 1H), 5.01 (d, 1H), 7.29 (d,2H), 7.60 (d, 2H). B-7 0.5-1.5 (m, 37H), 1.5-2.3 (m, 10H), 2.4-3.0 (m,12H), 3.24 (s, 3H), 3.44 (d, 1H), 3.52 (d, 1H), 3.7 (brs, 1H), 4.09(brs, 2H), 4.18 (brs, 2H), 4.29 (brs, 2H), 4.46 (d, 1H), 4.73 (d, 1H),4.83 (br t, 2H), 6.63 (d, 2H), 7.20 (d, 2H), 7.92 (s, 1H). B-8 0.5-1.6(m, 37H), 1.7-2.3 (m, 10H), 2.4-3.0 (m, 7H), 3.24 (s, 3H), 3.45 (brs,1H), 3.52 (d, 1H), 3.8 (brs, 1H), 4.0-4.2 (m, 4H), 4.35 (brs, 2H), 4.5(d, 1H), 4.75 (d, 1H), 4.8-5.0 (m, 1H), 7.56 (d, 2H), 7.65 (d, 2H), 8.7(s, 1H). B-9 0.5-1.6 (m, 36H), 1.7-2.3 (m, 10H), 2.4-3.0 (m, 7H),3.1-3.4 (m, 5H), 3.55 (d, 1H), 3.8 (brs, 1H), 4.0-4.3 (m, 5H), 4.45 (d,1H), 4.75 (d, 1H), 4.85 (brs, 1H), 7.05 (t, 2H), 7.41-7.70 (m, 3H), 8.3(s, 1H).  B-10 0.5-1.4 (m, 40H), 1.5-2.4 (m, 17H), 2.6-2.7 (m, 4H),2.85-2.95 (m, 1H), 3.05-3.15 (m, 1H), 3.2 (s, 3H), 3.45-3.55 (m, 2H),3.8 (brs, 1H), 3.9-4.3 (m, 5H), 4.45 (d, 1H), 4.45 (d, 1H), 4.65-4.85(m, 3H), 5.75 (d, 1H), 7.55 (brs, 1H)  B-11 0.5-1.4 (m, 42H), 1.5-2.4(m, 15H), 2.6-2.7 (m, 5H), 2.85-2.95 (m, 1H), 3.05-3.15 (m, 1H), 3.45(d, 1H), 3.55 (d, 1H), 3.75 (brs, 1H), 3.8-3.85 (m, 1H), 4.05-4.2 (m,3H), 4.25-4.35 (m, 2H), 4.45 (d, 1H), 4.75 (d, 1H), 4.85 (s, 2H), 5.45(s, 1H), 7.45 (brs, 1H)  B-12 0.5-1.2 (m, 34H), 1.5-2.3 (m, 13H),2.65-2.95 (m, 6H), 3.2 (s, 3H), 3.45- 3.55 (m, 2H), 3.8 (brs, 1H),4.0-4.2 (m, 4H), 4.25-4.45 (m, 2H), 4.45 (d, 1H), 4.75-4.95 (m, 3H),7.6-7.7 (m, 4H), 8.8 (s, 1H).  B-13{circumflex over ( )} 1.09 (br s, 32H), 1.22-1.87 (m, 10 H), 1.90 (s, 2 H), 1.93 (br d, 1 H), 2.18 (br d, 1H), 2.53 (s, 3 H), 2.57 (br d, 1 H), 2.62-2.70 (m, 1 H), 2.83 (br d, 1H), 3.09-3.15 (m, 4 H), 3.16-3.24 (m, 2 H), 3.30 (br s, 6 H), 3.50 (brd, 1 H), 3.56-3.63 (m, 1 H), 3.70-3.78 (m, 1 H), 3.92-4.03 (m, 1 H),4.15 (br s, 1 H), 4.32 (q, 1 H), 4.39 (d, 1 H), 4.83 (dd, 1 H), 4.89 (d,1 H), 5.08 (br d, 1 H), 7.29 (br d, 2 H), 7.60 (d, 2 H) B-13a{circumflex over ( )} 0.72-1.19 (m, 32 H), 1.20-1.88 (m, 11 H),1.89 (s, 2 H), 1.90-1.97 (m, 1 H), 2.53 (s, 3 H), 2.56 (br s, 1 H),2.60-2.70 (m, 1 H), 2.83 (br d, 1 H), 3.10-3.14 (m, 3 H), 3.15-3.20 (m,1 H), 3.22-3.27 (m, 3 H), 3.44-3.56 (m, 2 H), 3.63-3.69 (m, 1 H),3.70-3.77 (m, 1 H), 3.85-3.94 (m, 1 H), 3.94-4.03 (m, 1 H), 4.07-4.14(m, 1 H), 4.15-4.21 (m, 1 H), 4.21-4.29 (m, 1 H), 4.33 (br d, 1 H),4.60-4.70 (m, 1 H), 4.83 (dd, 1 H), 4.89 (br d, 1 H), 4.94-5.02 (m, 1H), 5.09 (d, 1 H), 7.24-7.33 (m, 2 H), 7.55-7.64 (m, 2 H) {circumflexover ( )}acetate saltThe following Formula (1-A2) compounds were prepared in accordance withthe Schemes and procedures defined herein; and wherein R⁰ is H, R¹ ismethyl and R⁷ is ethyl; are provided in Table C. Respective compoundnames are provided below the table.

TABLE C Formula (1-A2) Compounds Ex # R² R³ Mass [M + H]⁺ C-1 H phenyl898 C-2 methyl phenyl 912 C-3 methyl

980

Table C Example Names:

C-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;C-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;andC-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

TABLE C Example NMR's C-1{circumflex over ( )} ¹H NMR (600 MHz, DMSO-d₆)δ ppm 0.91 (s, 32 H), 1.21-1.53 (m, 5 H), 1.61-1.74 (m, 3 H), 1.79 (brdd, 1 H), 1.88 (s, 1 H, AcOH), 2.07-2.09 (m, 1 H), 2.14 (td, 1 H), 2.24(br d, 1 H), 2.34-2.40 (m, 1 H), 2.60-2.66 (m, 2 H), 2.70-2.74 (m, 2 H),2.83 (s, 3 H), 2.84-2.89 (m, 1 H), 3.17 (br d, 1 H), 3.21 (s, 3 H),3.25-3.30 (m, 2 H), 3.40-3.42 (m, 2 H), 3.49 (br d, 1 H), 3.59-3.65 (m,1 H), 3.98-4.17 (m, 4 H), 4.42 (d, 1 H), 4.65 (d, 1 H), 4.73 (br s, 1H), 4.76 (q, 1 H), 5.10 (br s, 2 H), 6.87-6.93 (m, 1 H), 7.17-7.24 (m, 2H), 7.41 (br d, 2 H), 8.24 (s, 1 H) C-2{circumflex over ( )} ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.69-1.44 (m, 37 H), 1.63-1.84 (m, 3 H), 1.89 (s, 2H, AcOH), 2.08-2.18 (m, 1 H), 2.27 (br d, 1 H), 2.36 (br dd, 1 H), 2.44(s, 3 H), 2.63 (br dd, 1 H), 2.67 (br d, 1 H), 2.69-2.75 (m, 1 H), 2.77(br d, 1 H), 2.82-2.91 (m, 1 H), 3.04 (s, 3 H), 3.13-3.23 (m, 2 H), 3.25(s, 3 H), 3.31 (br s, 6 H), 3.38-3.48 (m, 3 H), 3.84-3.95 (m, 1 H),3.98-4.13 (m, 3 H), 4.38 (br d, 1 H), 4.69 (br d, 1 H), 4.78 (q, 1 H),5.02 (br s, 1 H), 7.06 (t, 1 H), 7.14 (d, 2 H), 7.27-7.35 (m, 2 H)C-3{circumflex over ( )} ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-1.23 (m,32 H), 1.23-1.84 (m, 8 H), 1.87 (s, 1 H, AcOH), 2.10-2.20 (m, 1 H), 2.26(br d, 1 H), 2.36 (br dd, 1 H), 2.54 (s, 3 H), 2.60-2.68 (m, 2 H),2.70-2.77 (m, 2 H), 2.87 (br d, 1 H), 3.12 (s, 3 H), 3.17 (br d, 1 H),3.21 (s, 3 H), 3.26 (br d, 2 H), 3.28- 3.39 (m, 5 H), 3.41 (br d, 1 H),3.47 (br s, 1 H), 3.49-3.58 (m, 1 H), 3.90- 4.14 (m, 4 H), 4.41 (br d, 1H), 4.67 (br d, 1 H), 4.77 (q, 1 H), 5.16-5.31 (m, 1 H), 7.28 (br d, 2H), 7.60 (br d, 2 H) {circumflex over ( )}acetate salt

The following Formula (1-A3) compounds were prepared in accordance withthe Schemes and procedures defined herein; wherein R⁰ is H, R¹ is methyland R⁷ is propyl; are shown in Table D. Respective compound names areprovided below the Table.

TABLE D Formula (1-A3) Compounds Example # R² R³ Mass [M + H]⁺ D-1 Hphenyl  928 D-2 methyl phenyl  942 D-3* methyl

1010 *MIC ≤ 64 μg/mL for at least one BRD bacterial strain

Table D Example Names:

D-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;D-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;andD-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

TABLE D Example NMR's  D-1{circumflex over ( )} ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.69-1.22 (m, 32 H), 1.23-1.85 (m, 11 H), 1.89 (s, 2 H),1.91 (br s, 1 H), 2.15 (br d, 1 H), 2.45-2.48 (m, 2 H), 2.55 (br d, 1H), 2.60-2.68 (m, 1 H), 2.74 (br d, 2 H), 2.78 (s, 3 H), 2.83 (br d, 1H), 3.15-3.24 (m, 1 H), 3.26 (s, 3 H), 3.32 (br s, 5 H), 3.45 (br d, 1H), 3.71 (br s, 3 H), 3.96-4.07 (m, 1 H), 4.09 (br s, 1 H), 4.37- 4.47(m, 2 H), 4.80-4.89 (m, 2 H), 4.94 (br d, 1 H), 6.89 (t, 1 H), 7.21 (t,2 H), 7.44 (d, 2 H), 8.33 (s, 1 H) D-2{circumflex over ( )} ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.72-1.22 (m, 32 H), 1.22-1.85 (m, 10 H), 1.90 (s, 2H), 1.91-1.99 (m, 2 H), 2.19 (br d, 1 H), 2.43 (s, 3 H), 2.45-2.49 (m, 2H), 2.59 (br d, 1 H), 2.63-2.70 (m, 1 H), 2.75 (s, 2 H), 2.83 (br d, 1H), 3.06 (s, 3 H), 3.09-3.19 (m, 1 H), 3.33 (br d, 6 H), 3.36 (s, 3 H),3.41-3.52 (m, 2 H), 3.71-3.81 (m, 1 H), 3.82-3.94 (m, 1 H), 4.10 (br s,1 H), 4.31-4.40 (m, 2 H), 4.84 (br d, 1 H), 4.88 (br d, 2 H), 7.06 (t, 1H), 7.14 (br d, 2 H), 7.26-7.35 (m, 2 H) D-3{circumflex over ( )} ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.72-1.22 (m, 32 H), 1.22-1.87 (m, 11 H), 1.89(s, 2 H), 1.90-1.96 (m, 2 H), 2.16 (br d, 1 H), 2.44-2.48 (m, 2 H), 2.53(s, 3 H), 2.56 (br d, 1 H), 2.61-2.69 (m, 1 H), 2.74 (s, 2 H), 2.83 (brd, 1 H), 3.13 (s, 3 H), 3.19 (br t, 2 H), 3.29 (s, 3 H), 3.32 (br s, 3H), 3.43 (s, 1 H), 3.47 (br d, 1 H), 3.63 (br d, 1 H), 3.76 (br dd, 1H), 3.92- 4.03 (m, 1 H), 4.12 (br s, 1 H), 4.34-4.42 (m, 2 H), 4.80-4.86(m, 1 H), 4.87 (br d, 1 H), 5.08 (br d, 1 H), 7.29 (br d, 2 H), 7.60 (d,2 H) {circumflex over ( )}acetate salt

The following Formula (1-A4) compounds were prepared in accordance withthe Schemes and procedures defined herein; wherein R⁰ is H, R¹ is methyland X′ is chloro; are shown in Table E. Respective compound names areprovided below the table.

TABLE E Formula (1-A4) Compounds Example # R² R³ Mass [M + H]⁺ E-1 Hphenyl 889 E-2 methyl phenyl 903 E-3 methyl

971

Table E Example Names:

E-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;E-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;andE-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea.

TABLE E Example NMR's E-1{circumflex over ( )} ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.69-1.27 (m, 30 H), 1.45 (br s, 4 H), 1.57-1.81 (m, 3 H),1.83-1.89 (m, 2 H), 1.89 (s, 2 H), 1.91-1.97 (m, 1 H), 2.18 (br d, 1 H),2.54-2.61 (m, 1 H), 2.62-2.70 (m, 1 H), 2.79 (s, 3 H), 2.83 (br d, 1 H),3.17-3.24 (m, 2 H), 3.26 (s, 3 H), 3.32 (br s, 3 H), 3.45 (br d, 1 H),3.65-3.79 (m, 3 H), 3.80-3.87 (m, 1 H), 4.00-4.07 (m, 1 H), 4.10 (br s,1 H), 4.12 (s, 1 H), 4.44 (br d, 1 H), 4.50 (q, 1 H), 4.81- 4.87 (m, 1H), 4.90 (br d, 1 H), 4.95 (br s, 1 H), 6.90 (t, 1 H), 7.21 (t, 2 H),7.43 (d, 2 H), 8.30 (s, 1 H) E-2{circumflex over ( )} ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.71-1.25 (m, 32 H), 1.25-1.49 (m, 6 H), 1.65 (br d, 1H), 1.71-1.88 (m, 3 H), 1.89 (s, 1 H), 1.90-1.97 (m, 2 H), 2.20 (br d, 1H), 2.42 (s, 3 H), 2.56 (br d, 1 H), 2.66 (br dd, 1 H), 2.82 (br d, 1H), 3.06 (s, 3 H), 3.10-3.19 (m, 1 H), 3.35 (s, 3 H), 3.45 (br d, 1 H),3.53 (br dd, 1 H), 3.71-3.86 (m, 4 H), 3.92 (br d, 1 H), 4.12 (br s, 1H), 4.36 (br d, 1 H), 4.46 (br d, 1 H), 4.84 (br d, 1 H), 4.88 (br d, 1H), 4.91 (br d, 1 H), 7.06 (t, 1 H), 7.15 (br d, 2 H), 7.27-7.34 (m, 2H) E-3{circumflex over ( )} ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71-1.26(m, 32 H), 1.27-1.88 (m, 10 H), 1.89 (s, 2 H), 1.90-1.99 (m, 1 H), 2.18(br d, 1 H), 2.52 (br s, 3 H), 2.56 (br d, 1 H), 2.66 (br dd, 1 H), 2.83(br d, 1 H), 3.13 (s, 3 H), 3.16- 3.24 (m, 2 H), 3.28 (s, 3 H), 3.48 (brd, 1 H), 3.64-3.78 (m, 3 H), 3.80- 3.86 (m, 1 H), 3.97 (s, 1 H),3.98-4.07 (m, 1 H), 4.12 (br s, 1 H), 4.40 (br d, 1 H), 4.47 (q, 1 H),4.81-4.87 (m, 1 H), 4.91 (br d, 1 H), 5.08 (d, 1 H), 7.29 (br d, 2 H),7.60 (d, 2 H) {circumflex over ( )}acetate salt

The following Formula (1-A5) compounds were prepared in accordance withthe Schemes and procedures defined herein; wherein R⁰ is H and R¹ ismethyl; are shown in Table F. Respective compound names are providedbelow the table.

TABLE F Formula (1-A5) Compounds Example # R² R³ Mass [M + H]⁺ F-1 Hphenyl 895 F-2 methyl phenyl 909 F-3* methyl

977 *MIC ≤ 64 μg/mL for at least one BRD bacterial strain

Table F Example Names:

F-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;F-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;andF-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

TABLE F Example NMR's F-1{circumflex over ( )} ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.73-1.26 (m, 31 H), 1.27-1.52 (m, 4 H), 1.60-1.80 (m, 4 H), 1.86(br s, 1 H), 1.89 (s, 3 H), 1.91-1.97 (m, 1 H), 2.16 (br d, 1 H),2.52-2.60 (m, 1 H), 2.60-2.69 (m, 1 H), 2.77 (s, 3 H), 2.83 (br d, 1 H),3.18-3.22 (m, 1 H), 3.25 (s, 3 H), 3.27-3.30 (m, 1 H), 3.36 (br s, 1 H),3.37-3.42 (m, 3 H), 3.42-3.46 (m, 1 H), 3.63-3.82 (m, 2 H), 3.95-4.05(m, 1 H), 4.08 (br s, 1 H), 4.20 (s, 1 H), 4.45 (br d, 1 H), 4.47- 4.55(m, 1 H), 4.83 (br d, 1 H), 4.87 (br d, 1 H), 4.97 (br s, 1 H), 6.89 (t,1 H), 7.21 (t, 2 H), 7.45 (d, 2 H), 8.35 (s, 1 H) F-2{circumflex over( )} ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69-1.23 (m, 32 H), 1.29-1.49 (m,5 H), 1.59-1.86 (m, 4 H), 1.90 (s, 2 H), 1.91-1.95 (m, 1 H), 2.19 (br d,1 H), 2.43 (s, 3 H), 2.52-2.60 (m, 1 H), 2.62-2.70 (m, 1 H), 2.82 (br d,1 H), 3.07 (s, 3 H), 3.11-3.19 (m, 1 H), 3.25 (br d, 1 H), 3.36 (s, 3H), 3.38 (br s, 1 H), 3.42 (br s, 2 H), 3.43-3.46 (m, 1 H), 3.49-3.57(m, 1 H), 3.75 (br d, 1 H), 3.78 (s, 1 H), 3.87-3.96 (m, 1 H), 4.13 (brs, 1 H), 4.35 (br d, 1 H), 4.44 (q, 1 H), 4.83 (br d, 1 H), 4.90 (br d,2 H), 7.05 (t, 1 H), 7.15 (d, 2 H), 7.27- 7.34 (m, 2 H) F-3{circumflexover ( )} ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-1.27 (m, 32 H), 1.27-1.87(m, 10 H), 1.89 (s, 1 H), 1.90-1.98 (m, 1 H), 2.17 (br d, 1 H), 2.53 (brs, 3 H), 2.57 (br s, 1 H), 2.66 (br dd, 1 H), 2.83 (br d, 1 H), 3.14 (s,3 H), 3.21 (br dd, 1 H), 3.29 (br s, 3 H), 3.40 (br s, 2 H), 3.43-3.50(m, 2 H), 3.61-3.71 (m, 1 H), 3.75 (br dd, 1 H), 3.91 (br s, 1 H),3.96-4.07 (m, 1 H), 4.13 (br s, 1 H), 4.38 (br d, 1 H), 4.42-4.50 (m, 1H), 4.83 (br d, 1 H), 4.89 (br d, 1 H), 5.10 (br d, 1 H), 7.29 (br d, 2H), 7.60 (br d, 2 H)

The following Formula (1-A6) compounds were prepared in accordance withthe Schemes and procedures defined herein; wherein R^(c) is H and R¹ ismethyl; are shown in Table G. Respective compound names are providedbelow the table.

TABLE G Formula (1-A6) Compounds Example # R² R³ Mass [M + H]⁺ G-1 Hphenyl 879 G-2 methyl phenyl 893 G-3 methyl

961

Table G Example Names:

G-1.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;G-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;andG-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

TABLE G Example NMR's G-1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68-1.22 (m,32 H), 1.22-1.95 (m, 12 H), 2.13-2.23 (m, 1 H), 2.55 (br d, 1 H), 2.65(br dd, 1 H), 2.78 (s, 4 H), 2.82 (br d, 1 H), 3.16-3.23 (m, 1 H), 3.26(s, 3 H), 3.39-3.44 (m, 1 H), 3.70 (br s, 2 H), 3.95-4.07 (m, 1 H), 4.11(br s, 1 H), 4.18 (s, 1 H), 4.37 (s, 1 H), 4.42 (br d, 1 H), 4.48 (q, 1H), 4.83 (br d, 1 H), 4.88 (br d, 1 H), 5.00 (br d, 1 H), 6.90 (t, 1 H),7.21 (t, 2 H), 7.43 (br d, 2 H), 8.32 (s, 1 H) G-2{circumflex over ( )}¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.67-1.24 (m, 32 H), 1.25-1.86 (m, 10H), 1.88 (s, 1 H), 1.92 (br s, 1 H), 2.21 (br d, 1 H), 2.37-2.46 (m, 3H), 2.56 (br d, 1 H), 2.65 (br d, 1 H), 2.70-2.86 (m, 3 H), 3.07 (s, 3H), 3.11- 3.19 (m, 1 H), 3.26 (br s, 1 H), 3.36 (s, 3 H), 3.40-3.45 (m,1 H), 3.48- 3.58 (m, 1 H), 3.75 (br s, 1 H), 3.87-3.98 (m, 1 H), 4.07(br s, 1 H), 4.15 (br s, 1 H), 4.33 (br d, 1 H), 4.40-4.50 (m, 1 H),4.83 (br d, 1 H), 4.91 (br t, 2 H), 7.06 (br t, 1 H), 7.15 (br d, 2 H),7.24-7.36 (m, 2 H) G-3{circumflex over ( )} ¹H NMR (400 MHz, DMSO-d₆) δppm 0.68-1.26 (m, 32 H), 1.26-1.88 (m, 10 H), 1.89 (s, 2 H), 1.91-1.98(m, 1 H), 2.14-2.24 (m, 1 H), 2.52 (s, 3 H), 2.54-2.60 (m, 1 H),2.61-2.69 (m, 1 H), 2.77 (d, 2 H), 2.79-2.87 (m, 1 H), 3.14 (s, 3 H),3.16-3.25 (m, 2 H), 3.30 (s, 3 H), 3.42-3.48 (m, 1 H), 3.61-3.71 (m, 1H), 3.71-3.81 (m, 1 H), 3.97-4.08 (m, 1 H), 4.16 (br s, 1 H), 4.23 (s, 1H), 4.33-4.39 (m, 1 H), 4.41-4.48 (m, 1 H), 4.80-4.86 (m, 1 H),4.88-4.93 (m, 1 H), 5.09-5.15 (m, 1 H), 7.29 (d, 2 H), 7.60 (d, 2 H){circumflex over ( )}acetate salt

The following Formula (1-A1) compounds were prepared using the Schemesand procedures defined herein; R⁰ is H, methyl or propyl, as defined inTable H. The respective compound names (mass [M+H]⁺) are provided belowthe table.

TABLE H Formula (1-A1-1) Compounds Ex # R¹ R² R³ R⁰ is H H-1 methyl Hcyclopropyl H-2 methyl H phenyl H-3 methyl H phenyl H-4 methyl H phenylH-5* methyl H propyl H-6 methyl H —(CH₂)₂N(CH₃)₂ H-7* methyl H

H-8 propyl methyl 4-CF₃-phenyl H-9 methyl H H H-10 methyl H 4-F-phenylH-11 methyl methyl phenyl H-12 methyl H

H-13 methyl methyl

H-14 methyl

phenyl H-15* methyl H pyridin-2yl H-16 methyl ethyl phenyl H-17 methylisopropyl phenyl H-18* methyl methyl phenyl H-19* methyl methyl phenylH-20 methyl methyl phenyl H-21 methyl methyl phenyl H-22 methyl H HH-23* methyl methyl phenyl H-24 methyl methyl phenyl H-25 methyl methylphenyl H-26 methyl methyl phenyl H-27 methyl methyl phenyl H-28 methylmethyl phenyl H-29 methyl methyl phenyl H-30 methyl methyl phenyl H-31methyl methyl phenyl H-32 methyl methyl phenyl H-33 methyl methyl phenylH-34 methyl methyl phenyl H-35 methyl methyl phenyl H-36* methyl methylphenyl H-37 methyl methyl phenyl H-38 methyl methyl phenyl H-39 methylphenyl phenyl H-40 methyl phenyl benzyl H-41 methyl methyl phenyl H-42methyl methyl phenyl H-43 methyl methyl phenyl H-44* methyl methylphenyl H-45 methyl methyl pyridin-2yl H-46 methyl methyl

H-47 methyl methyl phenyl H-48 methyl methyl

H-49 methyl methyl

H-50 methyl methyl

H-51 methyl methyl

H-52 methyl methyl

H-53 methyl methyl pyridin-3yl H-54 methyl —CH₂CF₃ phenyl H-55 methylphenyl

H-56 methyl methyl

H-57 methyl methyl

H-58 methyl methyl

H-59 methyl methyl

H-60

methyl phenyl H-61* methyl methyl

H-62 methyl methyl

H-63 methyl methyl phenyl H-64

methyl phenyl H-65 benzyl methyl phenyl H-66 methyl methyl phenyl H-67methyl methyl

H-68 methyl methyl

H-69 propyl methyl phenyl H-70 isobutyl methyl phenyl H-71

methyl phenyl H-72 methyl H pyridin-3yl H-73 methyl H pyridin-4yl H-74methyl H

H-75* methyl H

H-76* methyl H 2-methoxy phenyl H-77 methyl H 4-cyanophenyl H-78* methylH 3-CF₃-phenyl H-79 methyl H 3-cyanophenyl H-80 methyl H 2-chlorophenylH-81 methyl H 2-methylphenyl H-82 methyl H 2-fluorophenyl H-83 methyl H4-fluorophenyl H-84 methyl H 4-chlorophenyl H-85 methyl H 3-fluorophenylH-86 methyl H 3-OMe-phenyl H-87* methyl H 4-OMe-phenyl H-88 methyl H3-chlorophenyl H-89* methyl H 4-methylphenyl H-90* methyl H3-methylphenyl H-91 methyl H phenyl H-92 methyl H methyl H-93 methyl Hcyclopropyl H-94 methyl H cyclobutyl H-95 methyl H 4-CF₃-phenyl H-96methyl H H H-97 methyl H —(CH₂)₂N(CH₃)₂ H-98* methyl H

H-99 methyl methyl 4-OHphenyl R⁰ is methyl H-100 methyl methyl

H-101 methyl methyl phenyl R⁰ is propyl H-102 methyl methyl phenyl H-103methyl methyl

Ex # R⁵ R⁶ R⁰ is H H-1

H-2 methyl methyl H-3 H —(CH₂)₂N(CH₃)₂ H-4 ethyl ethyl H-5* H—(CH₂)₂N(CH₃)₂ H-6 H propyl H-7* H propyl H-8 H propyl H-9 propyl—(CH₂)₂N(CH₃)₂ H-10 propyl

H-11 H propyl H-12 propyl

H-13 H propyl H-14 H propyl H-15* H propyl H-16 H propyl H-17 H propylH-18* H —(CH₂)₂OCH₃ H-19* H —(CH₂)₃OCH₃ H-20 methyl —(CH₂)₂N(CH₃)₂ H-21H —(CH₂)₂S(O)₂CH₃ H-22 propyl —C(O)NH₂ H-23* H ethyl H-24 H —CH₂CH(CH₃)₂H-25 H

H-26 H methyl H-27 H

H-28 H butyl H-29 H isopentyl H-30 H

H-31 H

H-32 H phenyl H-33 H

H-34 H

H-35 H

H-36* H

H-37 methyl cyclobutyl H-38 H

H-39 H propyl H-40 H propyl H-41 H

H-42 H

H-43 H

H-44* H

H-45 H propyl H-46 H propyl H-47 H

H-48 H propyl H-49 H propyl H-50 H propyl H-51 H propyl H-52 H propylH-53 H propyl H-54 H propyl H-55 H propyl H-56 H propyl H-57 H propylH-58 H propyl H-59 H propyl H-60 H propyl H-61* H propyl H-62 H propylH-63 propyl

H-64 H propyl H-65 H propyl H-66 H H H-67 H propyl H-68 H propyl H-69 Hpropyl H-70 H propyl H-71 H propyl H-72 H propyl H-73 H propyl H-74 Hpropyl H-75* H propyl H-76* H propyl H-77 H propyl H-78* H propyl H-79 Hpropyl H-80 H propyl H-81 H propyl H-82 H propyl H-83 H propyl H-84 Hpropyl H-85 H propyl H-86 H propyl H-87* H propyl H-88 H propyl H-89* Hpropyl H-90* H propyl H-91 H propyl H-92 H propyl H-93 H propyl H-94 Hpropyl H-95 H propyl H-96 H propyl H-97 H propyl H-98* H propyl H-99 Hpropyl R⁰ is methyl H-100 H propyl H-101 H propyl R⁰ is propyl H-102 Hpropyl H-103 H propyl *MIC ≤ 64 μg/mL for at least one BRD bacterialstrain

Table H Example Names:

H-1.3-cyclopropyl-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((3-cyclopropyl-1-(2-morpholinoethyl)ureido)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(1029);H-2.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((dimethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea(897);H-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea(940);H-4.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((diethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea(925);H-5.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea(906);H-6.3-(2-(dimethylamino)ethyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(906);H-7.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(2-(piperidin-1-yl)ethyl)urea(946);H-8.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-propyl-3-(4-(trifluoromethyl)phenyl)urea(1021);H-9.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)(propyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(878);H-10.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((3-(4-fluorophenyl)-1-propylureido)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea(1066);H-11.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(925);H-12.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((1-propyl-3-(4-(trifluoromethyl)phenyl)ureido)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea(1166);H-13.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea(993);H-14.1-cyclopropyl-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-1i1-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-phenylurea(951);H-15.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-2-yl)urea(913);H-16.1-ethyl-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-1i1-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-phenylurea(939);H-17.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-isopropyl-1-methyl-3-phenylurea(953);H-18.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((2-methoxyethyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(941);H-19.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((3-methoxypropyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(955);H-20.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(968);H-21.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(methylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(989);H-22.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((1-propylureido)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(878);H-23.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(911);H-24.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isobutylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(939);H-25.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((3-(1H-imidazol-1-yl)propyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(991);H-26.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(897);H-27.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopropylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(923);H-28.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((butylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(939);H-29.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopentylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(953);H-30.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((((1-methylpiperidin-4-yl)methyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(994);H-31.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((((1-acetylpiperidin-4-yl)methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1022);H-32.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((phenylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(959);H-33.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(995);H-34.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-cyclopropylethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(951);H-35.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(2-oxopyrrolidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1008);H-36.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((([1,1′-biphenyl]-4-ylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1049);H-37.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclobutyl(methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(951);H-38.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1008);H-39.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3,3-diphenylurea(987);H-40.1-benzyl-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea(939);H-41.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((cyclopropylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(937);H-42.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-morpholinoethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(996);H-43.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(phenylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1051);H-44.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)phenethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1055);H-45.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-2-yl)urea(926);H-46.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrazin-2-yl)urea(927);H-47.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(2-oxopyridin-1(2H)-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1018);H-48.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridazin-3-yl)urea(927);H-49.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea(927);H-50.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-5-yl)urea(927);H-51.1-(5-chloropyrimidin-2-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea(962);H-52.1-(5-cyclopropylpyrimidin-2-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea(967);H-53.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-3-yl)urea(926);H-54.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenyl-3-(2,2,2-trifluoroethyl)urea(993);H-55.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenyl-3-(tetrahydro-2H-pyran-4-yl)urea(995);H-56.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(1,2,4-triazin-3-yl)urea(928);H-57.1-(2,6-dimethylpyrimidin-4-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea(955);H-58.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)urea(929);H-59.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-4-yl)urea(926);H-60.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-(4-methoxybenzyl)-3-methyl-3-phenylurea(1031);H-61.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(thiazol-2-yl)urea(932);H-62.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(3-methylpyridin-4-yl)urea(940);H-63.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((3-methyl-3-phenyl-1-propylureido)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(1058);H-64.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-3-phenyl-1-(thiazol-2-ylmethyl)urea(1008);H-65.1-benzyl-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-3-phenylurea(1001);H-66.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(aminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(883);H-67.1-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea(967);H-68.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridazin-4-yl)urea(927);H-69.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-3-phenyl-1-propylurea(953);H-70.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-isobutyl-3-methyl-3-phenylurea(967)H-71.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-3-phenyl-1-(pyridin-3-ylmethyl)urea(1002);H-72.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-3-yl)urea(913);H-73.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-4-yl)urea(913);H-74.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)urea(916);H-75.3-(1,5-dimethyl-1H-pyrazol-3-yl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(930);H-76.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-methoxyphenyl)-1-methylurea(942);H-77.3-(4-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(937);H-78.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea(980);H-79.3-(3-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(937);H-80.3-(2-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(946);H-81.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(o-tolyl)urea(926);H-82.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-fluorophenyl)-1-methylurea(930);H-83.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea(930);H-84.3-(4-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(946);H-85.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-fluorophenyl)-1-methylurea(930);H-86.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-methoxyphenyl)-1-methylurea(942);H-87.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-methoxyphenyl)-1-methylurea(942);H-88.3-(3-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(946);H-89.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(p-tolyl)urea(925);H-90.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(m-tolyl)urea(926);H-91.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea(911);H-92.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea(849);H-93.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopropylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea(875);H-94.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclobutylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea(889);H-95.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)phenyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea(979);H-96.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(835);H-97.3-(2-(dimethylamino)ethyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(906);H-98.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(2-(piperidin-1-yl)ethyl)urea(946);H-99.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-hydroxyphenyl)-1,3-dimethylurea(941);H-100.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea(1007);H-101.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(939);H-102.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea(967); andH-103.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea(1035).

TABLE H Example NMR's ¹H NMR 400 MHz, DMSO-d6 (unless otherwisespecified) δ ppm H-1  0.17-2.24 (m, 47 H) 2.30-2.73 (m, 19 H) 2.75-2.91(m, 1 H) 3.04-4.21 (m, 24 H) 4.21-5.03 (m, 7 H) 6.16-6.40 (m, 1 H)7.06-7.26 (m, 1 H) H-2  0.64-2.43 (m, 44 H) 2.61-3.12(m, 6 H) 3.12-3.55(m, 11 H) 3.60-4.16 (m, 4 H) 4.26-4.63 (m, 3 H) 4.74-5.09 (m, 3 H)5.87-6.08 (m, 1 H) 6.76- 6.95 (m, 1 H) 7.09-7.27 (m, 2 H) 7.33-7.58 (m,2 H) 8.12-8.42 (m, 2 H) H-3  0.67-1.83 (m, 33 H) 1.83-2.04 (m, 9 H)2.04-2.22 (m, 7 H) 2.25-2.41 (m, 2 H) 2.54-2.74 (m, 5 H) 2.74-2.95 (m, 4H) 3.10-3.40 (m, 6 H) 3.40- 3.56 (m, 2 H) 3.64-3.86 (m, 2 H) 3.95-4.19(m, 3 H) 4.29-4.57 (m, 3 H) 4.75-5.05 (m, 3 H) 6.79-6.97 (m, 1 H)7.12-7.30 (m, 2 H) 7.37-7.53 (m, 2 H) 8.18-8.40 (m, 1 H) H-4  0.71-1.85(m, 42 H) 1.85-2.02 (m, 6 H) 2.07-2.21 (m, 1 H) 2.54-2.73 (m, 7 H)2.73-2.91 (m, 4 H) 3.13-3.52 (m, 13 H) 3.69-3.91 (m, 2 H) 3.97- 4.24 (m,2 H) 4.43-4.65 (m, 2 H) 4.77-5.00 (m, 3 H) 6.83-7.01 (m, 1 H) 7.11-7.30(m, 2 H) 7.33-7.58 (m, 2 H) 8.10-8.43 (m, 1 H) H-5{circumflex over ( )} 0.64-1.25 (m, 39 H), 1.26-1.52 (m, 8 H), 1.65-1.81 (m, 2 H), 1.88 (s, 9H), 1.92 (br s, 1 H), 1.94-2.03 (m, 1 H), 2.04-2.13 (m, 2 H), 2.15 (s, 6H), 2.16-2.19 (m, 1 H), 2.28-2.38 (m, 2 H), 2.59 (br t, 2 H), 2.64 (s, 3H), 2.64-2.73 (m, 4 H), 2.83 (br d, 1 H), 3.12 (br dd, 1 H), 3.31 (s, 3H), 3.34 (s, 1 H), 3.47 (br d, 1 H), 3.60-3.72 (m, 1 H), 3.94-4.06 (m, 1H), 4.12 (br s, 1 H), 4.35-4.44 (m, 2 H), 4.66 (br d, 1 H), 4.80-4.88(m, 2 H), 6.13 (br t, 1 H) H-6{circumflex over ( )}  0.68-1.43 (m, 38H), 1.44-1.88 (m, 6 H), 1.91 (s, 3 H), 2.00 (br d, 1 H), 2.13 (br d, 1H), 2.44 (br s, 4 H), 2.51 (br s, 3 H), 2.61-2.80 (m, 6 H), 2.80- 2.95(m, 3 H), 2.96-3.09 (m, 2 H), 3.16-3.23 (m, 2 H), 3.25 (s, 3 H),3.27-3.35 (m, 3 H), 3.35-3.42 (m, 2 H), 3.42-3.49 (m, 2 H), 3.62-3.73(m, 2 H), 3.94 (br d, 1 H), 4.18 (br d, 1 H), 4.31-4.38 (m, 1 H), 4.41(br d, 1 H), 4.72 (br s, 1 H), 4.90 (br d, 1 H), 5.02-5.10 (m, 1 H),6.09 (br s, 1 H) H-7{circumflex over ( )}  0.74-1.27 (m, 35 H),1.28-1.56 (m, 13 H), 1.71-1.83 (m, 2 H), 1.91 (s, 6 H), 1.92-2.03 (m, 2H), 2.17 (br d, 1 H), 2.27-2.45 (m, 7 H), 2.53-2.61 (m, 2 H), 2.64 (s, 3H), 2.66-2.73 (m, 1 H), 2.76 (br d, 1 H), 2.90 (br d, 1 H), 2.93-3.00(m, 1 H), 3.02-3.22 (m, 5 H), 3.27 (br s, 1 H), 3.33 (s, 3 H), 3.38 (brs, 2 H), 3.44 (br d, 1 H), 3.68 (br dd, 1 H), 3.93-4.04 (m, 1 H), 4.06(br s, 1 H), 4.38 (br d, 1 H), 4.43 (br d, 1 H), 4.74 (br s, 1 H), 4.86(br dd, 1 H), 4.89 (br d, 1 H), 6.13 (br s, 1 H) H-8  0.64-1.19 (m, 37H), 1.19-1.88 (m, 15 H), 1.90 (s, 2 H), 1.92 (br d, 1 H), 2.02 (br dd, 1H), 2.09-2.17 (m, 1 H), 2.39-2.46 (m, 1 H), 2.50-2.51 (m, 3 H),2.52-2.70 (m, 5 H), 2.76-2.86 (m, 2 H), 3.07 (s, 3 H), 3.18-3.21 (m, 1H), 3.23 (s, 3 H), 3.43 (br d, 1 H), 3.48-3.57 (m, 1 H), 3.62-3.79 (m, 2H), 4.07 (br s, 1 H), 4.32-4.41 (m, 2 H), 4.78-4.87 (m, 2 H), 4.99 (brd, 1 H), 7.27 (br d, 2 H), 7.60 (br d, 2 H) H-10{circumflex over ( )}0.71-1.26 (m, 33 H), 1.27-1.84 (m, 10 H), 1.89 (s, 3 H), 1.90-1.98 (m, 1H), 2.01-2.09 (m, 1 H), 2.15-2.22 (m, 1 H), 2.54-2.63 (m, 1 H), 2.67 (brdd, 1 H), 2.80 (s, 3 H), 2.84 (br s, 1 H), 3.19-3.26 (m, 2 H), 3.30 (s,3 H), 3.34 (br s, 3 H), 3.37-3.40 (m, 1 H), 3.44 (br d, 2 H), 3.47-3.58(m, 2 H), 3.65-3.80 (m, 2 H), 4.05-4.15 (m, 1 H), 4.18 (br s, 1 H), 4.42(br d, 1 H), 4.52-4.62 (m, 2 H), 4.87 (br d, 1 H), 4.96 (br s, 1 H),5.03 (br d, 1 H), 7.06 (td, 4 H), 7.42 (ddd, 4 H), 8.33 (s, 1 H),8.83-9.11 (m, 1 H) H-11 0.5-1.5 (m, 42H), 1.5-2.3 (m, 8H), 2.4-3.0 (m,10H), 3.05 (s, 3 H), 3.07 (s, 1 H), 3.09-3.15 (m, 1 H), 3.27-3.33 (m, 1H), 3.35 (s, 3 H), 3.44 (br d, 1 H), 3.47-3.57 (m, 1 H), 3.63 (br s, 1H), 3.81 (br s, 1 H), 3.88 (br t, 1 H), 4.10 (br s, 1 H), 4.36 (d, 1 H),4.39 (br d, 1 H), 4.83 (dd, 1 H), 4.87 (d, 1 H), 4.90 (d, 1 H), 7.06 (t,1 H), 7.15 (dd, 2 H), 7.24-7.36 (m, 2 H) H-12{circumflex over ( )}0.42-0.52 (m, 2 H), 0.72-1.34 (m, 55 H), 1.35-1.89 (m, 11 H), 1.92 (s, 1H), 1.93-2.00 (m, 1 H), 2.01-2.12 (m, 2 H), 2.16-2.26 (m, 1 H), 2.55-2.63 (m, 1 H), 2.65-2.73 (m, 1 H), 2.84 (br s, 3 H), 2.90 (br s, 1 H),3.18- 3.25 (m, 1 H), 3.29 (br s, 3 H), 3.45 (br d, 2 H), 3.56-3.66 (m, 1H), 3.68- 3.79 (m, 2 H), 4.05-4.15 (m, 1 H), 4.19 (br s, 1 H), 4.29 (brd, 1 H), 4.41- 4.49 (m, 1 H), 4.56-4.66 (m, 1 H), 4.72 (br s, 1 H),4.84-4.93 (m, 1 H), 5.01-5.13 (m, 2 H), 5.24 (br s, 1 H), 7.59-7.75 (m,7 H), 8.84 (br s, 1 H) H-13{circumflex over ( )} 0.74-1.26 (m, 33 H),1.28-1.54 (m, 7 H), 1.61-1.84 (m, 2 H), 1.90 (s, 3 H), 1.94 (br d, 2 H),1.99-2.07 (m, 1 H), 2.12-2.19 (m, 1 H), 2.41-2.49 (m, 2 H), 2.52 (s, 3H), 2.53-2.57 (m, 1 H), 2.58-2.72 (m, 4 H), 2.84 (br d, 1 H), 3.13 (s, 3H), 3.14-3.22 (m, 2 H), 3.27-3.28 (m, 1 H), 3.28 (s, 3 H), 3.33 (br s, 3H), 3.47 (br d, 1 H), 3.67 (br s, 1 H), 3.77 (br d, 1 H), 3.98 (br dd, 1H), 4.10 (br s, 1 H), 4.41 (br d, 2 H), 4.83 (br d, 1 H), 4.87 (br d, 1H), 5.06 (br d, 1 H), 7.30 (br d, 2 H), 7.60 (br d, 2 H) H-14{circumflexover ( )} 0.47-0.57 (m, 1H), 0.60-0.68 (m, 1H) 1.5 (m, 46H), 1.6-1.71(m, 1H), 1.72- 1.82 (m, 1H), 1.87 (s, 1.5H) 1.88-1.98 (m, 2H), 1.99-2.09(m, 1H), 2.13-2.23 (m, 1H), 2.37-2.78 (m, 12H), 2.79-2.89 (m, 1H),3.08-3.18 (m, 1 H), 3.25- 3.37 (s, 4 H), 3.38-3.46 (m, 1 H), 3.47-3.55(m, 1H), 3.85-3.40 (br s, 1 H), 4.01-4.10(m, 1 H), 4.29-4.47 (m, 2 H),4.77-4.95 (m, 2 H), 7.04 (t, 1 H), 7.16 (br d, 2 H), 7.25-7.36 (m, 2 H)H-15{circumflex over ( )} 0.5-1.5 (m, 40H), 1.5-2.3 (m, 11H), 2.4-3.0(m, 10H), 3.19-3.31 (m, 3H), 3.44 (d, 1H), 3.7 (brs, 1H), 4.08 (brs,3H), 4.16 (s, 1H), 4.45 (dd, 4H), 4.85 (br d, 3H), 5.3 (brs, 2H),6.91-6.94 (m, 1H), 7.64-7.68 (m, 2H), 8.16-8.3 (m, 1H), 8.18-8.33 (brs,1H). H-16 METHANOL-d₄ δ ppm 0.78-1.09 (m, 20 H) 1.09-1.60 (m, 22 H)1.71- 1.84 (m, 5 H) 1.87-1.98 (m, 2 H) 2.19-2.31 (m, 2 H) 2.31-2.38 (m,3 H) 2.58-2.68 (m, 2 H) 2.73-2.82 (m, 2 H) 2.87-3.05 (m, 3 H) 3.11-3.19(m, 1 H) 3.35-3.42 (m, 4 H) 3.46-3.66 (m, 4 H) 3.89-3.98 (m, 1 H) 4.03-4.10 (m, 1 H) 4.40-4.48 (m, 2 H) 4.84-4.90 (m, 1 H) 4.90-4.96 (m, 1 H)7.00-7.07 (m, 1 H) 7.07-7.14 (m, 2 H) 7.22-7.31 (m, 2 H) H-17METHANOL-d₄ δ ppm 0.78-1.35 (m, 41 H) 1.36-1.97 (m, 15 H) 2.25- 2.33 (m,4 H) 2.44-2.52 (m, 1 H) 2.78-2.89 (m, 3 H) 2.97-3.19 (m, 5 H) 3.38-3.54(m, 6 H) 3.86-3.96 (m, 1 H) 4.00-4.07 (m, 1 H) 4.17-4.29 (m, 1 H)4.37-4.43 (m, 1 H) 4.43-4.52 (m, 1 H) 4.85-4.92 (m, 1 H) 4.92- 4.97 (m,1 H) 7.03-7.15 (m, 3 H) 7.23-7.33 (m, 2 H) H-18{circumflex over ( )}0.5-1.5 (m, 36H), 1.7-2.3 (m, 12H), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 14H),3.5- 3.9 (m, 3H), 4.1-4.4 (m, 4H), 4.82-4.87 (m, 3H), 7.05 (t, 1H, J = 8Hz), 7.14 (d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8 Hz) H-19{circumflex over( )} ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.5-1.5 (m, 36H), 1.7-2.3 (m, 12H),2.4-2.8 (m, 12H), 3.0-3.4 (m, 14H), 3.5-3.9 (m, 3H), 4.1-4.4 (m, 4H),4.85- 4.86 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.30(t, 2H, J = 8 Hz) H-20{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3(m, 20H), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 14H), 3.5- 3.9 (m, 3H), 4.1-4.5(m, 4H), 4.81-4.84 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.16 (d, 2H, J = 8Hz), 7.30 (t, 2H, J = 8 Hz) H-21 ppm 0.5-1.5 (m, 36H), 1.7-2.3 (m, 9H),2.4-2.8 (m, 10H), 3.0-3.4 (m, 14H), 3.5-3.9 (m, 3H), 4.1-4.5 (m, 4H),4.81-4.88 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz) H-22 0.77-0.93 (m, 10 H), 0.93-1.11 (m, 20 H),1.12-1.22 (m, 7 H), 1.25- 1.40 (m, 4 H), 1.40-1.56 (m, 5 H), 1.61-1.76(m, 2 H), 1.76-1.85 (m, 2 H), 1.88 (s, 5 H), 1.96-2.06 (m, 1 H),2.06-2.19 (m, 1 H), 2.54-2.58 (m, 1 H), 2.64 (s, 4 H), 2.82 (br d, 1 H),3.41-3.47 (d, 1 H), 3.60-3.70 (m, 1 H), 3.74 (br s, 2 H), 3.90 (bs, 1H), 4.13 (br s, 1 H), 4.38 (br d, 1 H), 4.49 (br d, 1 H), 4.67 (br s, 1H), 4.83 (br d, 2 H), 4.93 (br d, 1 H), 5.68 (s, 2 H), 6.00 (br s, 2 H)H-23{circumflex over ( )} 0.5-1.5 (m, 44H), 1.7-2.3 (m, 12H), 2.4-2.8(m, 8H), 3.0-3.4 (m, 9H), 3.5- 3.9 (m, 4H), 4.1-4.5 (m, 4H), 4.81-4.87(m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J= 8 Hz) H-24{circumflex over ( )} 0.5-1.5 (m, 37H), 1.7-2.3 (m, 14H),2.4-2.8 (m, 8H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m, 4H), 4.1-4.5 (m, 7H),4.82-4.88 (m, 3H), 6.87 (brs, 1H), 7.05 (t, 1H, J = 8 Hz), 7.13-7.15 (m,3H), 7.28 (t, 2H, J = 8 Hz), 7.59 (s, 1H) H-25{circumflex over ( )}0.5-1.5 (m, 36H), 1.7-2.3 (m, 20H), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 14H),3.5- 3.9 (m, 3H), 4.1-4.5 (m, 4H), 4.81-4.84 (m, 3H), 7.05 (t, 1H, J = 8Hz), 7.16 (d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8 Hz) H-26{circumflex over( )} 0.5-1.5 (m, 37H), 1.7-2.3 (m, 14H), 2.4-2.8 (m, 8H), 3.0-3.4 (m,8H), 3.5- 3.9 (m, 4H), 4.1-4.5 (m, 4H), 4.81-4.87 (m, 3H), 7.05 (t, 1H,J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) H-27 0.2-1.5(m, 41H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 8H), 3.0-3.4 (m, 8H), 3.5-3.9 (m,4H), 4.1-4.5 (m, 4H), 4.81-4.87 (m, 3H), 7.06 (t, 1H, J = 8 Hz), 7.14(d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) H-28 ppm 0.5-1.5 (m, 43H),1.7-2.3 (m, 8H), 2.4-2.8 (m, 8H), 3.0-3.4 (m, 8H), 3.5-3.9 (m, 7H),4.1-4.5 (m, 4H), 4.81-4.87 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H,J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) H-29 0.5-1.5 (m, 45H), 1.7-2.3 (m,8H), 2.4-2.8 (m, 8H), 3.0-3.4 (m, 8H), 3.5-3.9 (m, 7H), 4.1-4.4 (m, 4H),4.81-4.86 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz) H-30 0.5-1.5 (m, 41 H), 1.7-2.3 (m, 12H), 2.4-2.8 (m,15H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m, 3H), 4.1-4.4 (m, 4H), 4.81-4.87 (m,3H), 7.07 (t, 1H, J = 8 Hz), 7.15 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8Hz) H-31{circumflex over ( )} 0.5-1.5 (m, 42H), 1.7-2.3 (m, 14H),2.4-2.8 (m, 10H), 3.0-3.4 (m, 10H), 3.5- 3.9 (m, 4H), 4.1-4.4 (m, 6H),4.81-4.88 (m, 3H), 7.06 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz) H-32{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3(m, 12H), 2.4-2.9 (m, 8H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m, 4H), 4.1-4.4(m, 4H), 4.83-5.0 (m, 3H), 6.55 (t, 1H, J = 7 Hz), 6.66 (d, 2H, J = 8Hz), 7.06-7.15 (m, 5H), 7.31 (t, 2H, J = 8 Hz) H-33{circumflex over ( )}0.5-1.5 (m,41 H), 1.6-2.3 (m, 12H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 14H),3.5- 3.9 (m, 5H), 4.1-4.4 (m, 3H), 4.84-4.88 (m, 3H), 7.05 (t, 1H, J = 8Hz), 7.14 (d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8 Hz) H-35 0.5-1.5 (m,39H), 1.7-2.3 (m, 12H), 2.4-2.9 (m, 12H), 3.0-3.4 (m, 10H), 3.5-3.9 (m,4H), 4.1-4.4 (m, 4H), 4.84-4.87 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14(d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8 Hz) H-36{circumflex over ( )}0.5-1.5 (m, 38H), 1.7-2.3 (m, 12H), 2.4-2.9 (m, 8H), 3.0-3.4 (m, 8H),3.5- 3.9 (m, 4H), 4.1-4.4 (m, 4H), 4.81-4.90 (m, 3H), 7.05 (t, 1H, J = 8Hz), 7.13 (d, 2H, J = 8 Hz), 7.27-7.36 (m, 3H), 7.42-7.47 (m, 4H),7.63-7.67 (m, 4H) H-37{circumflex over ( )} 0.5-1.5 (m, 39H), 1.7-2.3(m, 14H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 10H), 3.5- 3.9 (m, 4H), 4.1-4.4(m, 4H), 4.81-4.88 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8Hz), 7.29 (t, 2H, J = 8 Hz) H-38{circumflex over ( )} 0.5-1.5 (m, 45H),1.7-2.3 (m, 16H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 9H), 3.5- 3.9 (m, 4H),4.1-4.4 (m, 4H), 4.84-4.87 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H,J = 8 Hz), 7.30 (t, 2H, J = 8 Hz) H-39 METHANOL-d₄ δ ppm 0.78-1.15 (m,36 H) 1.29-1.47 (m, 5 H) 1.65- 2.14 (m, 11 H) 2.40-2.84 (m, 8 H)3.10-3.38 (m, 9 H) 3.92-4.39 (m, 2 H) 4.33-4.39 (m, 2 H) 4.84 (m, 2 H)5.09 (m, 1 H) 6.00 (m 4 H) 7.09 t, 2 H) 7.29 (t, 4 H) H-40 METHANOL-d₄ δppm 0.88-1.71 (36H, m), 1.79-2.27 (8H, m), 2.69- 2.99 (12H, m),3.22-3.74 (8H, m), 3.97-4.58 (6H, m), 4.99 (2H, m), 7.26- 7.37 (5H, m)H-41{circumflex over ( )} 0.09-1.5 (m, 41H), 1.7-2.3 (m, 12H), 2.4-2.9(m, 9H), 3.0-3.4 (m, 10H), 3.5- 3.9 (m, 4H), 4.1-4.4 (m, 3H), 4.84-4.87(m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.15 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J= 8 Hz) H-42{circumflex over ( )} 0.5-1.5 (m, 36H), 1.6-2.3 (m, 12H),2.4-2.9 (m, 16H), 3.0-3.4 (m, 9H), 3.5- 3.9 (m, 8H), 4.1-4.4 (m, 3H),4.79-4.86 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz) H-43{circumflex over ( )} 0.5-1.5 (m, 38H), 1.6-2.3(m, 12H), 2.4-2.9 (m, 9H), 3.0-3.5 (m, 10H), 3.6- 3.9 (m, 4H), 4.1-4.4(m, 3H), 4.82-4.86 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.13 (d, 2H, J = 8Hz), 7.29 (t, 2H, J = 8 Hz), 7.66 (t, 2H, J = 8 Hz), 7.73 (t, 1H, J = 7Hz), 7.90 (d, 2H, J = 8 Hz) H-44{circumflex over ( )} 0.8-1.5 (m, 37H),1.6-2.3 (m, 12H), 2.4-2.9 (m, 12H), 3.0-3.5 (m, 8H), 3.6- 3.9 (m, 4H),4.1-4.4 (m, 3H), 4.84-4.86 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.13 (d, 2H,J = 8 Hz), 7.29 (t, 2H, J = 8 Hz), 7.45 (d, 2H, J = 8 Hz), 7.62 (d, 2H,J = 8 Hz) H-45 0.5-1.5 (m, 43H), 1.7-2.3 (m, 9H), 2.4-2.9 (m, 9H),3.0-3.4 (m, 9H), 3.5-3.9 (m, 3H), 4.1-4.4 (m, 3H), 4.78-4.83 (m, 2H),5.07 (d, 1H, J = 4 Hz), 6.86 (t, 1H, J = 7 Hz), 7.03 (d, 1H, J = 8 Hz),7.58 (t, 1H, J = 8 Hz), 8.19 (d, 1H, J = 4 Hz) H-46{circumflex over ( )}0.5-1.5 (m, 43H), 1.7-2.3 (m, 19H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 9H),3.7- 3.9 (m, 3H), 4.1-4.4 (m, 3H), 4.81-4.83 (m, 2H), 5.2 (s, 1H), 8.04(d, 1H, J = 3 Hz), 8.24 (s, 1H), 8.36 (s, 1H) H-47 0.8-1.5 (m, 37H),1.6-2.3 (m, 9H), 2.4-2.9 (m, 10H), 3.0-3.5 (m, 8H), 3.6- 3.9 (m, 5H),4.1-4.4 (m, 4H), 4.79-4.86 (m, 3H), 6.17 (t, 1H, J = 8 Hz), 6.33 (d, 1H,J = 8 Hz), 7.02 (t, 1H, J = 8 Hz), 7.11 (d, 2H, J = 8 Hz), 7.25-7.35 (m,3H), 7.61 (d, 1H, J = 7 Hz) H-48 0.5-1.5 (m, 42H), 1.7-2.3 (m, 9H),2.4-2.9 (m, 9H), 3.0-3.4 (m, 9H), 3.5-3.9 (m, 3H), 4.1-4.4 (m, 4H),4.8-4.9 (m, 2H), 5.17 (d, 1H, J = 5 Hz), 7.34 (d, 1H, J = 9 Hz),7.44-7.48 (m, 1H), 8.75 (d, 1H, J = 4 Hz) H-49{circumflex over ( )}0.5-1.5 (m, 42H), 1.7-2.3 (m, 16H), 2.4-2.9 (m, 9H), 3.0-3.4 (m, 9H),3.7 (brs, 2H), 4.1-4.5 (m, 5H), 4.81-4.82 (m, 2H), 5.0 (brs, 1H), 6.87(brs, 1H), 8.45 (d, 2H, J = 4 Hz) H-50{circumflex over ( )} 0.5-1.5 (m,42H), 1.7-2.3 (m, 13H), 2.4-2.9 (m, 9H), 3.0-3.4 (m, 9H), 3.7- 3.9 (m,3H), 4.1-4.5 (m, 3H), 4.8-4.9 (m, 2H), 5.08 (s, 1H), 8.60 (s, 2H), 8.78(s, 1H) H-51{circumflex over ( )} 0.5-1.5 (m, 43H), 1.7-2.3 (m, 20H),2.4-2.9 (m, 9H), 3.0-3.4 (m, 9H), 4.1- 4.5 (m, 5H), 4.81-4.83 (m, 2H),8.53 (s, 2H) H-52 0.5-1.5 (m, 47H), 1.7-2.3 (m, 10H), 2.4-2.9 (m, 9H),3.0-3.4 (m, 9H), 3.65 (brs, 1H), 4.08-4.34 (m, 4H), 4.8-4.9 (m, 3H),8.27 (s, 2H) H-53 0.5-1.5 (m, 43H), 1.7-2.3 (m, 9H), 2.4-2.9 (m, 9H),3.0-3.4 (m, 9H), 3.5-3.9 (m, 3H), 4.1-4.4 (m, 4H), 4.8-4.9 (m, 2H), 5.17(d, 1H, J = 5 Hz), 7.34 (d, 1H, J = 9 Hz), 7.44-7.48 (m, 1H), 8.75 (d,1H, J = 4 Hz) H-54 METHANOL-d₄ δ ppm 0.92-1.70 (40H, m), 1.86-2.05 (6H,m), 2.30- 2.37 (2H, m), 2.91 (3H, s), 2.73-3.15 (7H, m), 3.49 (3H, m),3.63-3.75 (2H, m), 4.02-4.20 (3H, m), 4.53-4.71 (3H, m), 4.97-5.05 (2H,m), 7.17-7.41 (5H, m) H-55 METHANOL-d₄ δ ppm 0.90-1.42 (36H, m),1.52-1.74 (6H, m), 1.78- 2.05 (11H, m), 2.37-2.54 (5H, m), 2.78-3.25(8H, m), 3.42-3.60 (8H, m), 3.93-4.03 (3H, m), 4.14-4.18 (2H, m),4.51-4.60 (2H, m), 4.98- 5.06 (2H, m), 7.18-7.44 (5H, m) H-56{circumflexover ( )} 0.5-1.5 (m, 43H), 1.7-2.3 (m, 14H), 2.4-2.9 (m, 10H), 3.0-3.6(m, 10H), 4.1- 4.5 (m, 5H), 4.8-5.0 (m, 3H), 8.48 (s, 1H), 8.86 (s, 1H)H-57{circumflex over ( )} 0.5-1.5 (m, 43H), 1.7-2.3 (m, 17H), 2.4-2.9(m, 12H), 3.0-3.4 (m, 6H), 3.5- 3.7 (m, 4H), 4.1-4.5 (m, 3H), 4.81-4.84(m, 2H), 5.2 (brs, 1H), 6.61 (s, 1H) H-58{circumflex over ( )} 0.5-1.5(m, 43H), 1.7-2.3 (m, 12H), 2.4-2.9 (m, 12H), 3.0-3.5 (m, 6H), 3.6- 3.8(m, 6H), 4.1-4.5 (m, 3H), 4.84-4.89 (m, 3H), 7.30 (s, 1H), 7.63 (s, 1H)H-59{circumflex over ( )} 0.5-1.5 (m, 43H), 1.7-2.3 (m, 16H), 2.4-2.9(m, 9H), 3.0-3.4 (m, 9H), 3.7- 3.9 (m, 3H), 4.1-4.5 (m, 3H), 4.81-4.86(m, 2H), 5.2 (brs, 1H), 6.97 (d, 2H, J = 5 Hz), 8.27 (d, 2H, J = 6 Hz)H-60 CHLOROFORM-d 0.77-1.51 (m, 38H), 1.60-1.66 (m, 1H), 1.77-2.20 (m,10H), 2.46-2.59 (m, 2H), 2.64-2.76 (m, 3H), 2.86-2.91 (m, 3H), 3.06-3.13(m, 1H), 3.25-3.31 (m, 1H), 3.37 (s, 3H), 3.41-3.57 (m, 4H), 3.70-3.73(m, 3H), 3.93-4.09 (m, 3H), 4.31-4.38 (m, 1H), 4.42-4.45 (m, 1H),4.79-4.84 (m, 1H), 4.87-4.90 (m, 1H), 6.71-6.77 (m, 2H), 6.82-6.88 (m,2H), 6.93-6.98 (m, 2H), 7.01-7.08 (m, 1H), 7.19-7.25 (m, 2H)H-61{circumflex over ( )} 0.5-1.5 (m, 42H), 1.7-2.3 (m, 12H), 2.4-2.9(m, 9H), 3.0-3.5 (m, 9H), 3.7- 3.8 (m, 3H), 4.1-4.4 (m, 3H), 4.81-4.83(m, 2H), 5.03 (brs, 1H), 7.08 (d, 1H, J = 4 Hz), 7.34-7.35 (d, 1H, J = 4Hz), 8.46 (s, 1H) H-62{circumflex over ( )} 0.5-1.5 (m, 43H), 1.7-2.3(m, 20H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 6H), 3.7- 3.9 (m, 3H), 4.1-4.4(m, 3H), 4.81-4.87 (m, 2H), 7.14 (d, 1H, J = 5 Hz), 8.31-8.35 (m, 2H)H-63 0.6-1.5 (mm, 44H), 1.65 (m, 1H), 1.7-1.9 (mm, 3 H), 1.93 (m, 1H),2.07 (s, 1H), 2.18 (d, 1H), 2.44 (s, 3H), 2.55 (br, 1H), 2.66 (m, 1H),2.83 (br d, 1H), 2.95 (m, 1H), 3.02 (m, 1H), 3.07 (s, 3H), 3.10 (s, 3H),3.16 (m, 1H), 3.36 (s, 3H), 3.37 (s, 1H), 3.44 (d, 1H), 3.50 (br m, 1H),3.58 (d, 1H), 3.71 (br, 1H), 3.90 (m, 1H), 4.12 (m, 1H), 4.38 (m, 2H),4.85 (dd, 1H), 4.88 (d, 1H), 4.91 (d, 1H), 7.04, t, 1H), 7.10 (t, 1H),7.16 (d, 2H), 7.23 (2, 2H). 7.30 (q, 4H) H-64 CHLOROFORM-d 0.78-1.03 (m,20H), 1.12-1.22 (m, 13H), 1.25-1.30 (m, 3H), 1.37-1.50 (m, 4H),1.57-1.66 (m, 1H), 1.75-2.01 (m, 8H), 2.12-2.18 (m, 2H), 2.42-2.59 (m,2H), 2.61-2.79 (m, 4H), 2.99 (s, 3H), 3.07-3.13 (m, 1H), 3.21-3.34 (m,2H), 3.35-3.46 (m, 4H), 3.47-3.54 (m, 1H), 3.88-3.99 (m, 1H), 4.06-4.14(m, 1H), 4.19-4.35 (m, 4H), 4.38-4.45 (m, 2H), 4.78-4.83 (m, 1H),4.87-4.91 (m, 1H), 7.01-7.10 (m, 3H), 7.16-7.18 (m, 1H), 7.20-7.28 (m,2H), 7.57-7.61 (m, 1H) H-65 CHLOROFORM-d 0.79-1.08 (m, 17H), 1.09-1.65(m, 22H), 1.77-1.97 (m, 5H), 2.05-2.20 (m, 2H), 2.54-2.82 (m, 8H),2.84-2.87 (m, 3H), 3.03-3.10 (m, 2H), 3.25-3.33 (m, 2H), 3.33-3.37 (m,3H), 3.38-3.68 (m, 7H), 4.00-4.14 (m, 3H), 4.32-4.39 (m, 1H), 4.42-4.47(m, 1H), 4.73-4.79 (m, 1H), 4.89-4.94 (m, 1H), 6.81-6.88 (m, 2H),6.97-7.09 (m, 3H), 7.12-7.17 (m, 1H), 7.19-7.25 (m, 4H) H-66{circumflexover ( )} 0.99 (s, 29 H), 1.18-1.87 (m, 11 H), 1.89 (s, 2 H), 1.92 (brd, 1 H), 2.17 (br d, 1 H), 2.38-2.46 (m, 3 H), 2.53-2.58 (m, 1 H),2.62-2.70 (m, 2 H), 2.76- 2.86 (m, 2 H), 3.05 (s, 3 H), 3.09-3.16 (m, 2H), 3.23-3.32 (m, 1 H), 3.32 (br s, 2 H), 3.34 (s, 3 H), 3.46 (br d, 2H), 3.57-3.66 (m, 2 H), 3.67- 3.76 (m, 1 H), 3.88-3.98 (m, 1 H), 4.10(br s, 1 H), 4.21-4.30 (m, 1 H), 4.41 (br d, 1 H), 4.43-4.48 (m, 1 H),4.83 (br d, 1 H), 4.85-4.88 (m, 1 H), 7.06 (br t, 1 H), 7.16 (br d, 2H), 7.26-7.38 (m, 2 H) H-67{circumflex over ( )} 0.5-1.5 (m, 45H),1.7-2.3 (m, 20H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 10H), 4.1- 4.3 (m, 3H),4.80-4.83 (m, 2H), 4.97 (s, 1H), 8.26 (s, 1H) H-68{circumflex over ( )}.5-1.5 (m, 43H), 1.7-2.3 (m, 14H), 2.4-2.9 (m, 9H), 3.0-3.5 (m, 9H),4.1-4.5 (m, 4H), 4.8-4.9 (m, 2H), 5.3 (s, 1H), 7.09-7.11 (m, 1H), 8.82(d, 1H, J = 6 Hz), 8.95 (s, 1H) H-69{circumflex over ( )} 0.63-1.19 (m,37 H), 1.19-1.89 (m, 13 H), 1.90 (s, 2 H), 1.92 (br s, 1 H), 2.09-2.22(m, 2 H), 2.39-2.48 (m, 2 H), 2.50-2.51 (m, 3 H), 2.52-2.64 (m, 3 H),2.66 (s, 2 H), 2.82 (br d, 1 H), 3.00 (s, 3 H), 3.05-3.21 (m, 3 H),3.26-3.29 (m, 1 H), 3.36 (s, 3 H), 3.40 (br d, 1 H), 3.59-3.71 (m, 2 H),4.07 (br s, 1 H), 4.31 (br d, 1 H), 4.33-4.40 (m, 1 H), 4.80 (br d, 2H), 4.85 (br dd, 1 H), 7.09 (t, 1 H), 7.15 (br d, 2 H), 7.26-7.34 (m, 2H) H-70 METHAN0L-d4 δ ppm 0.66-0.75 (m, 6 H) 0.79-0.86 (m, 3 H)0.90-1.11 (m, 16 H) 1.11-1.35 (m, 18 H) 1.38-1.98 (m, 12 H) 2.24-2.37(m, 2 H) 2.49-2.58 (m, 1 H) 2.74-2.86 (m, 2 H) 2.90-3.01 (m, 2 H)3.02-3.13 (m, 5 H) 3.23-3.29 (m, 2 H) 3.32-3.46 (m, 6 H) 3.71-3.83 (m, 1H) 3.99- 4.05 (m, 1 H) 4.32-4.39 (m, 1 H) 4.41-4.51 (m, 1 H) 4.86-4.91(m, 1 H) 4.92-4.97 (m, 1 H) 7.01-7.09 (m, 1 H) 7.13-7.20 (m, 2 H)7.22-7.32 (m, 2 H) H-71 CHLOROFORM-d 0.77-1.47 (m, 36H), 1.55-1.94 (m,6H), 2.11-2.26 (m, 2H), 2.35-2.60 (m, 4H), 2.65-2.75 (m, 3H), 2.79-2.84(m, 3H), 2.95-3.03 (m, 3H), 3.26-3.45 (m, 6H), 3.50-3.57 (m, 1H),3.90-3.99 (m, 1H), 4.05-4.17 (m, 2H), 4.18-4.24 (m, 1H), 4.28-4.40 (m,1H), 4.43-4.53 (m, 1H), 4.66-4.76 (m, 1H), 4.89-4.98 (m, 1H), 5.95-6.09(m, 1H), 6.85-6.93 (m, 2H), 6.93-7.05 (m, 2H), 7.05-7.11 (m, 1H),7.18-7.24 (m, 2H), 7.49-7.61 (m, 1H), 8.32-8.49 (m, 1H) H-72 0.5-1.5 (m,43H), 1.5-2.3 (m, 11H), 2.4-3.0 (m, 10H), 3.2-3.35 (m, 5H), 3.5 (d, 1H),3.6 (brs, 1H), 4.15 (brs, 3H), 4.43 (d, 2H), 4.82-4.90 (m, 3H), 7.22-7.25 (m, 1H), 7.87 (d, 1H), 8.11-8.12 (s, 1H), 8.49 (s, 1H), 8.60-8.61(m, 1H). H-73 0.5-1.5 (m, 40H), 1.5-2.3 (m, 11H), 2.4-3.0 (m, 10H),3.1-3.2 (m, 2H), 3.49-3.5 (m, 4H), 3.75 (brs, 2H), 4.09-4.1 (m, 4H),4.42 (s, 2H), 4.81-4.86 (m, 4H), 7.44 (s, 2H), 8.28 (d, 2H), 8.78 (brs,1H). H-74 0.5-1.5 (m, 41H), 1.5-2.3 (m, 14H), 2.4-3.0 (m, 13H),3.14-3.16 (brt, 1H), 3.25 (s, 1H), 3.33 (d, 3H), 3.46 (d, 1H), 3.73 (s,4H), 4.08 (brs, 2H), 4.42 (t, 2H), 4.82-4.88 (m, 3H), 7.29 (s, 1H), 7.63(s, 1H), 8.2 (s, 1H). H-75 0.5-1.5 (m, 40H), 1.5-2.3 (m, 12H), 2.4-3.0(m, 13H), 3.13-3.25 (brs, 1H), 3.29 (brs, 3H), 3.56 (d, 2H), 3.68 (s,3H), 3.7 (brs, 2H), 4.12 (br t, 1H), 4.22 (brs, 2H), 4.41 (d, 2H),4.81-4.87 (m, 4H) 6.05 (s, 1H), 8.46 (s, 1H). H-76 0.5-1.5 (m, 41H),1.5-2.3 (m, 8H), 2.4-3.0 (m, 16H), 3.19-3.20 (m, 3H), 3.28-3.33 (m, 4H),3.47 (d, 2H), 3.72 (s, 4H), 4.11 (d, 3H), 4.42 (d, 2H), 4.82-4.87 (m,2H), 6.80-6.85 (m, 2H), 6.87-6.93 (m, 1H), 7.77 (d, 1H), 8.1 (brs, 1H).H-77 0.5-1.5 (m, 43H), 1.5-2.3 (m, 8H), 2.4-3.0 (m, 13H), 3.19-3.21 (m,3H), 3.44 (d, 2H), 3.48 (brs, 2H), 4.07 (brs, 3H), 4.40 (m, 2H),4.78-4.83 (m, 3H), 7.62 (s, 4H), 8.83 (s, 1H). H-78 0.5-1.5 (m, 40H),1.5-2.3 (m, 8H), 2.4-3.0 (m, 13H), 3.22-3.25 (m, 5H), 3.46 (d, 3H), 3.60(brs, 3H), 4.10 (brs, 2H), 4.42 (d, 2H), 4.81-4.86 (m, 3H), 7.22 (d,1H), 7.44 (t, 1H), 7.76 (d, 1H), 7.88 (s, 1H), 8.68 (s, 1H). H-790.5-1.5 (m, 43H), 1.5-2.3 (m, 10H), 2.4-3.0 (m, 10H), 3.25 (s, 4H), 3.43(d, 1H), 3.73 (brs, 1H), 4.04 (brs, 2H), 4.43 (d, 2H), 4.82-4.92 (m,3H), 7.33- 7.35 (m, 1H), 7.41-7.45 (m, 1H), 7.74-7.76 (m, 1H), 7.91 (s,1H), 8.68 (brs, 1H). H-80 0.5-1.5 (m, 44H), 1.5-2.3 (m, 10H), 2.4-3.0(m, 16H), 3.17-3.26 (m, 4H), 3.46 (d, 1H), 3.61 (brs, 1H), 4.04-4.10 (m,2H), 4.42 (d, 2H), 4.81-4.86 (m, 2H), 6.97 (t, 1H), 7.23 (t, 1H), 7.38(d, 1H), 7.72 (t, 1H), 8.3 (brs, 1H). H-81 0.5-1.5 (m, 44H), 1.5-2.3 (m,11H), 2.4-3.0 (m, 11H), 3.2-3.31 (m, 6H), 3.5 (d, 2H), 3.7 (brs, 2H),4.03 (brs, 1H), 4.12 (brs, 1H), 4.39-4.44 (m, 2H), 4.81-4.85 (m, 2H),6.92-6.96 (m, 1H), 7.07-7.13 (m, 2H), 7.29 (d, 1H), 7.91 (brs, 1H). H-820.5-1.5 (m, 40H), 1.5-2.3 (m, 8H), 2.4-3.0 (m, 10H), 3.21 (brd, 2H),3.26- 3.38 (m, 4H), 3.46 (d, 2H), 3.71 (brs, 2H), 4.0-4.10 (m, 3H), 4.42(d, 2H), 4.81-4.86 (m, 3H), 6.69 (m, 1H), 7.22-7.23 (m, 2H), 7.42 (d,1H), 8.54 (s, 1H). H-83 0.5-1.5 (m, 40H), 1.5-2.3 (m, 11H), 2.4-3.0 (m,10H), 3.21 (br d, 2H), 3.26-3.38 (m, 4H), 3.46 (d, 2H), 3.71 (brs, 2H),4.0-4.10 (m, 3H), 4.42 (d, 2H), 4.81-4.86 (m, 3H), 6.69 (m, 1H),7.22-7.23 (m, 2H), 7.42 (d, 1H), 8.54 (s, 1H). H-84 0.5-1.5 (m, 44H),1.5-2.3 (m, 10H), 2.4-3.0 (m, 10H), 3.17-3.26 (m, 4H), 3.46 (d, 1H),3.61 (brs, 1H), 4.04-4.10 (m, 2H), 4.42 (d, 2H), 4.81-4.86 (m, 2H), 7.25(d, 2H), 7.47 (d, 2H), 8.42 (s, 1H). H-85 0.5-1.5 (m, 40H), 1.5-2.3 (m,14H), 2.4-3.0 (m, 10H), 3.21 (br d, 2H), 3.26-3.38 (m, 4H), 3.46 (d,2H), 3.71 (brs, 2H), 4.0-4.10 (m, 3H), 4.42 (d, 2H), 4.81-4.86 (m, 3H),6.69 (m, 1H), 7.22-7.23 (m, 2H), 7.42 (d, 1H), 8.54 (s, 1H). H-860.5-1.5 (m, 40H), 1.5-2.3 (m, 8H), 2.4-3.0 (m, 10H), 3.19-3.20 (m, 3H),3.28-3.33 (m, 4H), 3.47 (d, 2H), 3.69 (s, 4H), 4.11 (d, 3H), 4.42 (d,2H), 4.82-4.87 (m, 2H), 6.48 (d, 1H), 7.00 (d, 1H), 7.07-7.14 (m, 2H),8.27 (s, 1H). H-87 0.5-1.5 (m, 41H), 1.5-2.3 (m, 8H), 2.4-3.0 (m, 13H),3.19-3.20 (m, 3H), 3.28-3.33 (m, 4H), 3.47 (d, 2H), 3.69 (s, 4H), 4.11(d, 3H), 4.42 (d, 2H), 4.82-4.87 (m, 2H), 6.80 (d, 2H), 7.31 (d, 2H),8.11 (s, 1H). H-88 0.5-1.5 (m, 44H), 1.5-2.3 (m, 10H), 2.4-3.0 (m, 13H),3.17-3.26 (m, 4H), 3.46 (d, 1H), 3.61 (brs, 1H), 4.04-4.10 (m, 2H), 4.42(d, 2H), 4.81-4.86 (m, 2H), 6.93 (d, 1H), 7.22 (t, 1H), 7.39 (d, 1H),7.63 (s, 1H), 8.56 (s, 1H). H-89 0.5-1.5 (m, 40H), 1.5-2.3 (m, 8H),2.4-3.0 (m, 13H), 3.19-3.23 (brs, 2H), 3.28-3.31 (brs, 3H), 3.47-3.48(d, 2H), 3.85 (brd, 3H), 4.11 (brs, 2H), 4.42 (brs, 1H), 4.44 (d, 2H),4.86-4.87 (m, 3H), 7.01 (d, 2H), 7.30 (d, 2H), 8.17 (s, 1H). H-900.5-1.5 (m, 44H), 1.5-2.3 (m, 11H), 2.4-3.0 (m, 11H), 3.2-3.31 (m, 6H),3.5 (d, 2H), 3.7 (brs, 2H), 4.03 (brs, 1H), 4.12 (brs, 1H), 4.39-4.44(m, 2H), 4.81-4.85 (m, 2H), 6.92-6.96 (m, 1H), 7.07-7.13 (m, 2H), 7.29(d, 1H), 7.91 (brs, 1H). H-91 0.5-1.5 (m, 42H), 1.5-2.3 (m, 11H),2.4-3.0 (m, 11H), 3.1-3.3 (m, 5H), 3.48 (d, 1H), 3.72 (br s, 1H), 4.1(m, 3H), 4.44 (br, 3H), 4.87 (d, 4H), 6.90 (dd, 1H), 7.21 (dd, 2H), 7.43(d, 2H), 8.29 (s, 1H) H-92 0.88-1.54 (m, 38 H) 1.57-2.11 (m, 12 H)2.59-2.85 (m, 8 H) 2.87-2.97 (m, 1 H) 2.99-3.10 (m, 2 H) 3.13-3.23 (m, 2H) 3.27-3.38 (m, 5 H) 3.43- 3.72 (m, 5 H) 3.73-3.91 (m, 2 H) 4.09-4.17(m, 1 H) 4.24-4.37 (m, 1 H) 4.55-4.68 (m, 1 H) 4.72-4.80 (m, 1 H)4.95-5.03 (m, 1 H) 5.03-5.10 (m, 1 H) H-93 0.88-1.54 (m, 38 H) 1.57-2.11(m, 12 H) 2.59-2.85 (m, 8 H) 2.87-2.97 (m, 1 H) 2.99-3.10 (m, 2 H)3.13-3.23 (m, 2 H) 3.27-3.38 (m, 5 H) 3.43- 3.72 (m, 5 H) 3.73-3.91 (m,2 H) 4.09-4.17 (m, 1 H) 4.24-4.37 (m, 1 H) 4.55-4.68 (m, 1 H) 4.72-4.80(m, 1 H) 4.95-5.03 (m, 1 H) 5.03-5.10 (m, 1 H) H-94 0.88-1.54 (m, 40 H)1.57-2.11 (m, 12 H) 2.59-2.85 (m, 8 H) 2.87-2.97 (m, 1 H) 2.99-3.10 (m,2 H) 3.13-3.23 (m, 2 H) 3.27-3.38 (m, 5 H) 3.43- 3.72 (m, 5 H) 3.73-3.91(m, 2 H) 4.09-4.17 (m, 1 H) 4.24-4.37 (m, 1 H) 4.55-4.68 (m, 1 H)4.72-4.80 (m, 1 H) 4.95-5.03 (m, 1 H) 5.03-5.10 (m, 1 H) H-95{circumflexover ( )} 0.70-1.27 (m, 33 H), 1.27-1.53 (m, 6 H), 1.58-1.82 (m, 3 H),1.89 (s, 3 H), 1.90-1.95 (m, 1 H), 2.04-2.18 (m, 2 H), 2.38-2.48 (m, 1H), 2.52- 2.64 (m, 2 H), 2.66 (s, 2 H), 2.81 (s, 3 H), 2.83-2.87 (m, 1H), 3.17-3.24 (m, 3 H), 3.26 (s, 4 H), 3.31-3.35 (m, 3 H), 3.44-3.49 (m,3 H), 3.68- 3.79 (m, 2 H), 4.01-4.07 (m, 1 H), 4.08-4.15 (m, 2 H),4.38-4.48 (m, 2 H), 4.80-4.85 (m, 1 H), 4.87 (br d, 1 H), 4.95 (br d, 1H), 7.56 (d, 2 H), 7.63-7.70 (m, 2 H), 8.73 (br s, 1 H) H-96 0.65-1.55(m, 42H), 1.61-1.86 (m, 2 H), 1.88 (s, 7 H) 1.97-2.22 (m, 2 H),2.35-2.45 (m, 1H), 2.58-2.70 (m, 7 H), 2.82 (br d, 1 H), 3.03-3.22 (m, 2H), 3.38-3.57 (m, 2 H), 3.57-3.79 (m, 3 H), 3.94 (br s, 3 H), 4.13 (brs, 2 H), 4.39 (br dd, 2 H), 4.68 (br s, 1 H), 4.75-5.03 (m, 3 H), 5.70(s, 2 H)  H-100 CHLOROFORM-d 0.68-1.51 (m, 36 H) 1.55-2.44 (m, 22 H)2.47-3.08 (m, 6 H) 3.13-3.47 (m, 6 H) 3.64-3.89 (m, 2 H) 3.90-4.19 (m, 1H) 4.20- 4.38 (m, 1 H) 4.45-4.57 (m, 1 H) 4.62-4.81 (m, 1 H) 4.79-4.94(m, 1 H) 4.92-5.21 (m, 4 H) 7.15-7.24 (m, 2 H) 7.44-7.52 (m, 2 H)  H-101CHLOROFORM-d 0.66-1.75 (m, 40 H)1.76-2.38 (m, 14 H) 2.42-3.04 (m, 10 H)3.09-3.67 (m, 7 H) 3.70-3.93 (m, 1 H) 4.00-4.22 (m, 3 H) 4.34- 4.46 (m,1 H) 4.46-4.61 (m, 1 H) 4.63-4.86 (m, 2 H) 4.91-5.12 (m, 1 H) 6.97-6.97(m, 1 H) 7.02-7.09 (m, 2 H) 7.14-7.36 (m, 2 H)  H-102{circumflex over( )} 0.69-1.22 (m, 37 H), 1.22-1.58 (m, 9 H), 1.72-1.81 (m, 1 H), 1.91(s, 4 H), 1.94-2.01 (m, 1 H), 2.02-2.12 (m, 2 H), 2.14-2.21 (m, 1 H),2.36- 2.42 (m, 1 H), 2.43 (s, 3 H), 2.44-2.48 (m, 1 H), 2.53-2.81 (m, 7H), 3.05 (s, 3 H), 3.09-3.17 (m, 1 H), 3.26 (br d, 3 H), 3.34 (br s, 3H), 3.48 (br dd, 2 H), 3.52-3.59 (m, 1 H), 3.91 (br d, 2 H), 3.99 (br d,1 H), 4.31 (br s, 1 H), 4.38 (br d, 1 H), 4.41 (br d, 1 H), 4.79 (br d,1 H), 4.83-4.90 (m, 2 H), 7.06 (t, 1 H), 7.15 (d, 2 H), 7.26-7.35 (m, 2H)  H-103{circumflex over ( )} 0.63-1.26 (m, 37 H), 1.28-1.56 (m, 10 H),1.69-1.83 (m, 2 H), 1.90 (s, 3 H), 1.94-2.19 (m, 5 H), 2.40-2.46 (m, 2H), 2.53 (br s, 3 H), 2.55-2.61 (m, 2 H), 2.69 (br s, 5 H), 3.12 (s, 3H), 3.14-3.22 (m, 2 H), 3.22-3.25 (m, 1 H), 3.26 (s, 3 H), 3.46-3.53 (m,2 H), 3.64-3.72 (m, 1 H), 3.88-3.95 (m, 1 H), 3.95-4.02 (m, 2 H), 4.31(br s, 1 H), 4.34-4.42 (m, 1 H), 4.45 (br d, 1 H), 4.78 (br d, 1 H),4.83-4.90 (m, 1 H), 5.05 (br d, 1 H), 7.29 (br d, 2 H), 7.60 (br d, 2 H)

The following Formula (1-A1a) compounds were prepared using the Schemesand procedures defined herein; and wherein R^(c) is H and R⁵ is H; areshown in Table 1. The respective compound names are provided below thetable.

TABLE I Formula (1-A1a) Compounds Ex # Ring A ± (R¹⁰)_(n) R⁶ Mass [M +H]⁺ I-1

methyl  904 I-2*

propyl  932 I-3

propyl  937 I-4

propyl  951 I-5

propyl 1001  I-6

propyl  953 I-7

propyl  937 *MIC ≤ 64 μg/mL for at least one BRD bacterial strain

Table I Example Names:

I-1.4-ethyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpiperazine-1-carboxamide;I-2.4-ethyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpiperazine-1-carboxamide;I-3.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylindoline-1-carboxamide;I-4.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-3,4-dihydroquinoline-1(2H)-carboxamide;I-5.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4-carboxamide1,1-dioxide;I-6.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide;I-7.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylisoindoline-2-carboxamide

TABLE I Example NMR's. ¹H NMR 400 MHz, DMSO-d6 (or otherwise specified)δ ppm I-2 0.86-1.48 (m, 37 H) 1.80-2.37 (18 H) 2.55-3.10 (m, 11 H) 3.18(m, 1 H) 3.21 (m, 1 H) 3.33 (s, 3 H) 3.42 (m, 1 H) 3.42 (m, 1 H) 3.48(m, 1 H) 3.53 (m, 1 H) 3.77 (m, 1 H) 3.80 (m, 1 H) 3.81 (m, 1 H) 4.04(m, 1 H) 4.15 (m, 1 H) 4.17 (m, 1 H) 4.42 (m, 1 H) 4.89 (m, 1 H) 5.04(m, 1 H) I-3 0.78-0.94 (m, 10 H), 0.94-1.18 (m, 23 H), 1.23 (br s, 4 H),1.31-1.65 (m, 7 H), 1.66-1.84 (m, 4 H), 1.94 (br s, 3 H), 2.13 (br d, 2H), 2.59-2.71 (m, 3 H), 2.76 (s, 4 H), 2.82-2.92 (m, 1 H), 2.92-3.05 (m,3 H), 3.19 (s, 3 H), 3.46 (br s, 1 H), 3.66-3.77 (m, 2 H), 3.78-3.96 (m,3 H), 4.08 (br s, 2 H), 4.42 (br d, 2 H), 4.80-4.89 (m, 2 H), 5.03 (brd, 1 H), 6.82 (br t, 1 H), 7.00- 7.08 (m, 2 H), 7.16 (br d, 1 H) I-40.76-0.94 (m, 11 H) 0.94-1.18 (m, 23 H) 1.23 (br s, 4 H) 1.31-1.49 (m, 5H) 1.49-1.65 (m, 2 H) 1.74 (brd, J = 9.54 Hz, 4 H) 1.85-2.02 (m, 3 H)2.13 (br d, J = 15.65 Hz, 3 H) 2.59-2.71 (m, 3 H) 2.76 (s, 4 H)2.80-2.92 (m, 1 H) 2.92-3.18 (m, 4 H) 3.18-3.39 (m, 15 H) 3.46 (br s, 2H) 3.59-3.77 (m, 3 H) 3.78-3.96 (m, 3 H) 4.08 (br s, 2 H) 4.42 (br d, J= 6.85 Hz, 3 H) 4.64- 4.91 (m, 3 H) 5.03 (br, d, J = 4.89 Hz, 1 H) 6.82(br t, J = 7.09 Hz, 1 H) 6.96- 7.10 (m, 2 H) 7.16 (br d, J = 7.09 Hz, 1H). I-5 0.77-0.96 (m, 8 H) 0.96-1.22 (m, 21 H) 1.27-1.53 (m, 5 H)1.61-1.88 (m, 6 H) 1.97-2.22 (m, 3 H) 2.39-2.65 (m, 10 H) 2.66-2.87 (m,3 H) 3.22 (s, 4 H) 3.28-3.36 (m, 4 H) 3.44-3.56 (m, 2 H) 3.63-3.79 (m, 2H) 3.81- 4.04 (m, 2 H), 4.06-4.21 (m, 1 H) 4.21-4.34 (m, 1 H) 4.34-4.48(m, 2 H) 4.74-4.94 (m, 2 H) 5.03 (d, J = 5.14 Hz, 1 H) 6.80 (br t, J =7.46 Hz, 1 H) 6.96-7.08 (m, 3 H) 7.98 (br s, 1 H) I-6 0.76-0.94 (m, 17H) 0.94-1.15 (m, 31 H) 1.19 (s, 5 H) 1.29-1.57 (m, 9 H) 1.63-1.81 (m, 5H) 1.81-1.95 (m, 5 H) 2.01 (br d, J = 11.25 Hz, 2 H) 2.06-2.25 (m, 2 H)2.39-2.59 (m, 18 H) 2.60-2.74 (m, 10 H) 2.78-2.96 (m, 4 H) 3.13-3.38 (m,11 H), 3.49 (br d, J = 5.87 Hz, 2 H) 3.64-3.71 (m, 3 H) 3.75 (br s, 2 H)3.82-3.98 (m, 3 H) 3.98-4.18 (m, 4 H) 4.20-4.34 (m, 1 H) 4.34-4.50 (m, 3H), 4.74-4.93 (m, 3 H) 5.25 (br d, J = 4.89 Hz, 2 H) 7.00-7.16 (m, 2 H)7.21 (br s, 1 H) 7.45 (br t, J = 7.70 Hz, 2 H) 7.70 (d, J = 7.82 Hz, 2H) 7.95 (s, 1 H). I-7 METHANOL-d₄ 0.92-2.09 (51H, m), 2.34 (1H, m), 2.61(1H, m), 2.89- 3.61 (16H, m), 3.82-3.99 (2H, m), 4.15 (1H, m), 4.58-4.73(4H, m), 4.93- 5.04 (4H, m), 7.29 (4H, m)

The following Formula (1-A1b) compounds were prepared using the Schemesand procedures defined herein; and wherein R⁰ is H; are shown in TableJ. The respective compound names are provided below the table.

TABLE J Formula (1-A1b) Compounds Ex # R² R³ Ring B ± (R⁹)_(n) Mass [M +H]⁺ J-1 H cyclohexyl

 958 J-2 H ethyl

 904 J-3 H t-butyl

 932 J-4 methyl phenyl

1009 J-5 H H

 876 J-6 H

 995 J-7 H phenyl

 952 J-8 H pyridin-3yl

 953 J-9 H ethyl

 975 J-10 methyl phenyl

 953 J-11* methyl phenyl

 969 J-12 methyl phenyl

 937 J-13 methyl phenyl

1030 J-14* methyl phenyl

1019 J-15 methyl phenyl

 959 J-16 methyl phenyl

 987 J-17* methyl phenyl

 987 J-18* methyl phenyl

 951 J-19 methyl phenyl

1006 J-20 methyl phenyl

1027 J-21 methyl phenyl

1029 J-22 methyl phenyl

 923 J-23 methyl phenyl

 934 J-24 methyl phenyl

 934 J-25* methyl phenyl

 999 J-26 methyl phenyl

 966 J-27 methyl phenyl

 935 J-28 methyl phenyl

 935 J-29 methyl phenyl

 936 J-30 methyl phenyl

 936 *MIC ≤ 64 μg/mL for at least one of the bacterial strains

Table J Example Names:

J-1.3-cyclohexyl-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;J-2.3-ethyl-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;J-3.3-(tert-butyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;J-4.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((3-morpholinoazetidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-5.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;J-6.3-(4-(dimethylamino)phenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;J-7.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;J-8.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-3-yl)urea;J-9.3-ethyl-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;J-10.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(morpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-11.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(thiomorpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-12.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(pyrrolidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-13.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-14.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-(trifluoromethyl)piperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-15.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((3,3-difluoroazetidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-16.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-17.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((4,4-difluoropiperidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-18.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-19.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((3-(piperidin-1-yl)azetidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-20.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-phenylpiperidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-21.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-(methylsulfonyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-22.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azetidin-1-ylmethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-23.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-pyrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-24.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-imidazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-25.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-26.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((3-(dimethylamino)azetidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-27.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-28.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;J-29.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-tetrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;andJ-30.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((2H-tetrazol-2-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea.

TABLE J Example NMR's ¹H NMR (400 MHz, DMSO-d6) δ ppm J-1  0.67-1.99 (m,54 H) 1.99-2.74 (m, 25 H) 2.75-2.96 (m, 2 H) 3.03- 3.57 (m, 12 H)3.62-4.17 (m, 6 H) 4.35-4.53 (m, 3 H) 4.59-4.77 (m, 1 H) 4.77-4.92 (m, 2H) 4.96-5.16 (m, 1 H) 5.65-5.92 (m, 1 H) J-2  0.67-1.54 (m, 34 H)1.58-1.83 (m, 3 H) 1.83-1.98 (m, 5 H) 2.07-2.19 (m, 3 H) 2.19-2.69 (m,17 H) 2.77-2.89 (m, 1 H) 2.96-3.17 (m, 4 H) 3.41-3.52 (m, 3 H) 3.64-3.76(m, 2 H) 3.97-4.18 (m, 2 H) 4.33-4.52 (m, 2 H) 4.52-4.71 (m, 1 H)4.78-4.98 (m, 2 H) 6.03-6.28 (m, 1 H) J-3  0.67-1.57 (m, 112 H)1.59-2.19 (m, 35 H) 2.19-2.74 (m, 47 H), 2.79- 3.00 (m, 2 H) 3.07-3.18(m, 1 H) 3.19-3.52 (m, 12 H) 3.64-3.76 (m, 2 H) 3.81-4.01 (m, 1 H)4.06-4.15 (m, 1 H) 4.33-4.52 (m, 5 H) 4.70- 4.89 (m, 5 H) 4.97-5.06 (m,2 H) 5.43-5.54 (m, 1 H) J-4  0.5-1.5 (m, 36H), 1.7-2.3 (m, 9H), 2.4-2.9(m, 10H), 3.0-3.4 (m, 14H), 3.5-3.9 (m, 8H), 4.1-4.4 (m, 4H), 4.84-4.86(m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.13 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J= 8 Hz) J-5  0.65-1.61 (m, 34 H) 1.61-1.82 (m, 2 H) 1.82-2.00 (m, 9 H)2.05-2.19 (m, 4 H) 2.19-2.73 (m, 20 H), 2.77-2.94 (m, 1 H) 3.04-3.22 (m,1 H) 3.22-3.39 (m, 4 H) 3.42-3.52 (m, 1 H) 3.63-3.79 (m, 1 H) 3.80-4.06(m, 1 H) 4.06-4.16 (m, 1 H) 4.34-4.51 (m, 2 H) 4.62-4.79 (m, 1 H)4.79-4.92 (m, 2 H) 5.63-5.75 (m, 2 H). J-6  0.72-1.82 (m, 36 H)1.84-1.99 (m, 6 H) 2.00-2.17 (m, 4 H) 2.17-2.71 (m, 17 H) 2.71-2.92 (m,10 H) 3.11-3.81 (m, 18 H) 4.02-4.18 (m, 2 H) 4.41-4.56 (m, 2 H)4.75-4.99 (m, 3 H) 6.55-6.72 (m, 2 H) 7.14-7.33 (m, 2 H) 7.85-8.06 (m, 1H) J-7  0.66-1.54 (m, 29 H) 1.55-1.83 (m, 4 H) 1.83-2.02 (m, 5 H)2.05-2.20 (m, 4 H) 2.20-2.73 (m, 16 H) 2.73-2.96 (m, 4 H) 2.96-3.52 (m,16 H) 3.67-3.85 (m, 2 H) 3.98-4.16 (m, 2 H) 4.39-4.54 (m, 2 H) 4.73-5.02(m, 3 H) 6.83-7.00 (m, 1 H) 7.13-7.30 (m, 2 H) 7.37-7.58 (m, 2 H)8.16-8.43 (m, 1 H) J-8  0.73-1.57 (m, 37 H) 1.55-1.87 (m, 5 H) 1.85-2.03(m, 8 H) 2.03-2.74 (m, 24 H) 2.72-2.94 (m, 4 H) 3.13-3.53 (m, 7 H)3.69-3.88 (m, 1 H) 4.03-4.17 (m, 2 H) 4.38-4.55 (m, 2 H) 4.77-4.94 (m, 3H) 7.13-7.35 (m, 1 H) 7.83-7.97 (m, 1 H) 8.07-8.19 (m, 1 H) 8.45-8.55(m, 1 H) 8.55-8.73 (m, 1 H) J-10{circumflex over ( )} 0.5-1.5 (m, 36H),1.7-2.3 (m, 15H), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 14H), 3.5-3.9 (m, 3H),4.1-4.4 (m, 4H), 4.81-4.87 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H,J = 8 Hz), 7.30 (t, 2H, J = 8 Hz) J-11{circumflex over ( )} 0.5-1.5 (m,36H), 1.7-2.3 (m, 12H), 2.4-2.8 (m, 16H), 3.0-3.4 (m, 8H), 3.5-3.9 (m,4H), 4.1-4.5 (m, 3H), 4.81-4.87 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14(d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) J-12 0.5-1.5 (m, 40H), 1.7-2.3(m, 9H), 2.4-2.8 (m, 12H), 3.0-3.4 (m, 7H), 3.5-3.9 (m, 4H), 4.1-4.4 (m,4H), 4.82-4.85 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.15 (d, 2H, J = 8 Hz),7.29 (t, 2H, J = 8 Hz) J-13{circumflex over ( )} 0.5-1.5 (m, 36H),1.7-2.3 (m, 12H), 2.4-2.8 (m, 11H), 3.0-3.4 (m, 8H), 3.5-3.9 (m, 8H),4.1-4.4 (m, 4H), 4.82-4.88 (m, 3H), 6.61 (t, 1H, J = 4.7 Hz), 7.05 (t,1H, J = 8 Hz), 7.15 (d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8 Hz), 8.35 (d,2H, J = 4.76 Hz) J-14 0.5-1.5 (m, 40H), 1.7-2.3 (m, 9H), 2.4-2.8 (m,12H), 3.0-3.4 (m, 9H), 3.5-3.9 (m, 4H), 4.1-4.4 (m, 3H), 4.82-4.87 (m,3H), 7.05 (t, 1H, J = 8 Hz), 7.15 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8Hz) J-15{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3 (m, 12H),2.4-2.8 (m, 9H), 3.0-3.4 (m, 7H), 3.5- 3.9 (m, 8H), 4.1-4.4 (m, 3H),4.82-4.88 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.13 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz) J-16{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3(m, 12H), 2.4-2.8 (m, 8H), 3.0-3.4 (m, 10H), 3.5-3.9 (m, 6H), 4.1-4.4(m, 3H), 4.83-4.93 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.15 (d, 2H, J = 8Hz), 7.30 (t, 2H, J = 8 Hz), 8.39 (s, 2H) J-17{circumflex over ( )}0.5-1.5 (m, 36H), 1.7-2.3 (m, 16H), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 10H),3.5-3.9 (m, 4H), 4.1-4.4 (m, 3H), 4.81-4.88 (m, 3H), 7.05 (t, 1H, J = 8Hz), 7.14 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) J-18 0.5-1.5 (m,43H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 12H), 3.0-3.4 (m, 6H), 3.5-3.9 (m,4H), 4.1-4.4 (m, 4H), 4.81-4.84 (m, 3H), 7.05 (t, H, J = 8 Hz), 7.15 (d,2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) J-19{circumflex over ( )} 0.5-1.5(m, 43H), 1.7-2.3 (m, 14H), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 12H), 3.5-3.9(m, 4H), 4.1-4.4 (m, 3H), 4.81-4.84 (m, 3H), 7.06 (t, 1H, J = 8 Hz),7.15 (d, 2H, J = 8 Hz), 7.28 (t, 2H, J = 8 Hz) J-20{circumflex over ( )}0.5-1.5 (m, 42H), 1.7-2.3 (m, 12H), 2.4-2.8 (m, 9H), 3.0-3.4 (m, 10H),3.5-3.9 (m, 4H), 4.1-4.4 (m, 3H), 4.82-4.87 (m, 3H), 7.06 (t, 1H, J = 8Hz), 7.15-7.19 (m, 3H,), 7.24-7.31 (m, 6H) J-21{circumflex over ( )}0.5-1.5 (m, 40H), 1.7-2.3 (m, 14H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 12H),3.5-3.9 (m, 4H), 4.1-4.4 (m, 3H), 4.81-4.88 (m, 3H), 7.05 (t, 1H, J = 8Hz), 7.15 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz) J-22{circumflex over( )} 0.5-1.5 (m, 36H), 1.7-2.3 (m, 14H), 2.4-2.9 (m, 10H), 3.0-3.4 (m,10H), 3.5-3.9 (m, 4H), 4.1-4.4 (m, 3H), 4.81-4.84 (m, 3H), 7.05 (t, 1H,J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29 (t, 2H, J = 8 Hz)J-23{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3 (m, 11H), 2.4-2.9(m, 7H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m, 3H), 4.1-4.5 (m, 6H), 4.82-4.94(m, 3H), 6.26 (s, 1H), 7.05-7.07 (m, 1H), 7.14 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz), 7.43 (s, 1H), 7.78 (s, 1H) J-24{circumflex over ( )}0.5-1.5 (m, 36H), 1.7-2.3 (m, 11H), 2.4-2.9 (m, 7H), 3.0-3.4 (m, 8H),3.5- 3.9 (m, 4H), 4.1-4.5 (m, 5H), 4.83-5.02 (m, 3H), 6.84 (s, 1H), 7.06(t, 1H, J = 7 Hz), 7.13 (d, 2H, J = 8 Hz), 7.25 (s, 1H), 7.30 (t, 2H, J= 8 Hz), 7.69 (s, 1H) J-25{circumflex over ( )} 0.5-1.5 (m, 35H),1.7-2.3 (m, 14H), 2.4-2.9 (m, 10H), 3.0-3.4 (m, 8H), 3.5-3.9 (m, 6H),4.1-4.5 (m, 4H), 4.82-4.90 (m, 3H), 7.03 7.16 (m, 7H), 7.29 (t, 2H, J =8 Hz) J-26{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3 (m, 18H),2.4-2.9 (m, 10H), 3.0-3.4 (m, 10H), 3.5-3.9 (m, 4H), 4.1-4.4 (m, 4H),4.81-4.86 (m, 3H), 7.05 (t, 1H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 7.29(t, 2H, J = 8 Hz) J-27{circumflex over ( )} 0.5-1.5 (m, 36H), 1.7-2.3(m, 14H), 2.4-2.9 (m, 7H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m, 4H), 4.1-4.5(m, 5H), 4.83-4.94 (m, 3H), 6.84 (s, 1H), 7.06 (t, 1H, J = 7 Hz), 7.13(d, 2H, J = 8 Hz), 7.25 (s, 1H), 7.30 (t, 2H, J = 8 Hz), 7.69 (s, 1H)J-28{circumflex over ( )} .5-1.5 (m, 36H), 1.7-2.3 (m, 11H), 2.4-2.9 (m,7H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m, 3H), 4.1-4.5 (m, 4H), 4.59-4.98 (m,5H), 7.05 (t, 1H, J = 7 Hz), 7.13 (d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8Hz), 7.72 (s, 1H), 8.06 (s, 1H) J-29{circumflex over ( )} 0.5-1.5 (m,36H), 1.6-2.3 (m, 13H), 2.4-2.9 (m, 7H), 3.0-3.4 (m, 8H), 3.5- 3.9 (m,3H), 4.1-4.5 (m, 4H), 4.63-4.99 (m, 5H), 7.05 (t, 1H, J = 7 Hz), 7.13(d, 2H, J = 8 Hz), 7.30 (t, 2H, J = 8 Hz), 7.72 (s, 1H), 9.24 (s, 1H)J-30{circumflex over ( )} 0.5-1.5 (m, 36H), 1.6-2.3 (m, 16H), 2.4-2.9(m, 7H), 3.0-3.5 (m, 8H), 3.9- 4.0 (m, 3H), 4.1-4.5 (m, 4H), 4.82-4.93(m, 5H), 7.05 (t, 1H, J = 7 Hz), 7.13 (d, 2H, J = 8 Hz), 7.30 (t, 2H, J= 8 Hz), 7.72 (s, 1H), 8.92 (s, 1H)

Biological

BRD pathogens include, for example, Pasteurella multocida; Mannheimiahaemolytica; Histophilus somni; and Mycoplasma bovis. There is somedebate as to whether M. bovis is a primary pathogen, secondary invaderor predisposing factor for other BRD agents. The polymicrobial nature ofBRD makes it difficult to ascribe a specific pathogen(s) to anindividual case of BRD, since affected animals typically presentnon-specific clinical signs. The epidemiology of BRD is well known, withcases occurring within 6-10 day of entry into the feedlot (FIG. 1).Therefore, antimicrobial metaphylaxis is routine for on-arrival cattlethat are deemed high risk of developing BRD. Low risk cattle may also beadministered a parenteral metaphylaxis. Macrolides tend to be theprimary antimicrobials that are administered to high risk cattle.

Primary screening of the compounds of the invention included theevaluation of antibacterial activity of analogs through determination ofmicrobial inhibition concentration (MIC) as per CLSI guidelines. Thescreening panel included the relevant BRD pathogens: 1) M. haemolytica(e.g., 12726, 46571 and 49023, all AHDRCC; and 33396 (ATCC)); and 2) P.multocida (e.g., 34135 and 46572 (both AHDRCC) and 43137 (ATCC)). Insome instances, H. somni (A700025K) pathogens were also included in thescreening panel. The AHDRCC strains originated from the Zoetis BRD/SRDsurveillance program and refer to the Animal Health Development andResearch Culture Collection. In addition, the screen assessed S. aureus(29213 ATCC) as a representative Gram-positive isolate, E. faecalis(19433 ATCC) as a commensal gram-positive gastrointestinal bacterium andE. coli (100, 3110 and 25922 (ATCC)) for the evaluation of effluxpotential. The screening panel BRD pathogens were assessed indetermining antibacterial activity of the Formula (1) compounds.

All relevant BRD pathogens were initially screened at a topconcentration of 64 μg/mL of a Formula (1) compound in an eleven-pointdilution series. The analogs were then characterized based on theirminimum inhibitory concentration (MIC) values to the BRD pathogens withthe goal to be >64 μg/mL for progression, and to be considered anon-antibiotic compound. Formula (1) compounds were considered to benon-antibacterial if the pathogen MIC was >64 μg/mL for M. haemolyticaand P. multocida strains. In addition, if Formula (1) compounds werealso tested against the H. somni strain, to be considerednon-antibacterial, the MIC was also >64 μg/mL. Generally, if the analogshad an MIC >64 μg/mL for the BRD pathogens, then the MIC's reported forS. aureus, E. faecalis and E. coli were also >64 μg/mL. In mostinstances, compounds of the invention with an initial screening BRDpathogen MIC result >64 μg/mL were not tested beyond this topconcentration since this MIC value was determinant for lack ofantibacterial activity. In addition, it should be noted that someExamples described in the Tables that are flagged as antibacterial(i.e., MIC ≤64 μg/mL) may actually be non-antibacterial but forpotential residual (minor impurity(s)) antibacterial starting material(i.e., tulathromycin epoxide, M9 epoxide, M8 epoxide or azithromycin)that was used in its preparation. If an Example was purified further,the MICs moved up essentially two dilutions across all strains tested inthe screening panel.

In-Vitro MIC Model

Compounds were analyzed for antibacterial activity against a panel ofAnimal Health specific Gram-positive and Gram-negative clinical strainsby diluting compounds in DMSO to an appropriate stock concentration todetermine the Minimal Inhibitory Concentration (MIC) via asemi-automated broth micro-dilution method (CLSI reference method) withQC strains and anti-microbial agent(s). Specifically, bacteria weregrown overnight on TSA w/5% sheep blood agar plates and diluted insaline buffer to a McFarland Standard 0.5, then further diluted incation-ion adjusted Mueller Hinton Broth to a final concentration ofapproximately 5×10⁵ CFU/mL. 100 μL of inoculated media was added to96-well plate(s) with 3 μL of serially diluted compound in each row.Depending on strain (see CLSI reference method), bacteria were incubated18-22 hours at 35-37° C. in ambient air, with 5% CO₂ or anaerobically(up to 48 hours).

In-Vitro Immunological Assay(s)

Whole Blood Assay—Fresh whole bovine blood samples were collected intoheparinized vacutainer tubes. Assay plates were prepared with 25 μL ofdrug diluted in PBS at varying concentration in 96 round bottom wells,then 225 μL of blood was added and plates incubated at 37° C. for 4hours. Cells were stimulated with LPS (or PBS for controls) by adding 25μL to the plates at a final concentration of 1 μg/mL and incubated at37° C. for 18 hours. To collect plasma, plates were centrifuged at2,000×g for 10 minutes and 100 μL of supernatant was transferred to a 96well polypropylene plate that was sealed and stored at −80° C. Sampleswere assayed for cytokines using the Meso Scale Discovery (MSD) platform(described below) from plasma collected directly from drug treatedanimals as well as plasma collected from the whole blood assay.

Cytokine Detection—An MSD U-Plex cytokine assay was developed followingthe MSD U-Plex protocol guide and included biotinylated captureantibodies against: bovine Interleukin (IL)-1β (Biorad), bovine IL-6(R&D Systems) and bovine tumor necrosis factor (TNF)-α (R&D Systems).The anti-IL-1β antibody was biotinylated using EZ-Link Sulfo-NHS-Biotin(Thermo Scientific) at a challenge ratio of 1:20 according tomanufacturer instructions. Assay calibrators (Kingfisher) were dilutedto a concentration of 40,000 μg/mL in control lithium heparin plasma,followed by 4-fold serial dilutions into plasma. The detectionantibodies were sulfo-tagged following the MSD quick guide conjugationprotocol using a challenge ratio of 1:20. Antibodies were used at thefollowing concentrations: anti-IL-1β at 1 μg/mL, anti-IL-6 at 1 μg/mLand anti-TNF-α at 0.5 μg/mL. Cytokines were quantified according tomanufacturer's instructions using a chemiluminescent readout. In brief,0.5 mL of all biotinylated antibodies were diluted to 10 μg/mL withDiluent 100 and paired to their respective linkers by adding 750 μL ofsupplied Linker solution and incubated for 30 minutes followed byaddition of Stop solution for another 30 minutes. The linked antibodieswere then diluted 10-fold into Stop solution. Plates were coated byadding 50 μL of antibody solutions per well and incubated covered andshaking for 1 hour at room temperature. Plates were washed three timeswith PBS/Tween20 prior to samples or standards being added at 30 μL perwell and incubated as above. Plates were washed three times beforedetection antibodies were added along with 2% goat and rabbit serum toblock and incubated same as above. Plates were washed a further threetimes before addition of 150 μL 2× Read buffer and read immediately onthe S16000 instrument (MSD). For soluble protein levels, a BCA proteinkit (Thermofisher,) was used. The cytokine concentrations (pg/mL) werenormalized to the total protein levels for each sample.

CD163 Expression by Flow Cytometry—Fresh whole bovine blood samples wereplaced on ice and processed within two hours of collection. Blood wasplaced in 96 well round bottom plates at 30 μL per well, 5 μL of goatserum was added as a blocking reagent and the plate was rocked at 4° C.for approximately 15 minutes. To label cells, 10 μL of a master mixpanel of antibodies including anti-CD14 (BioLegend #301854), anti-CD172a(BioRad #MCA2041C), anti-CD163 (Kingfisher #WSC0832B-100) and anti-CD16(BioRad #MCA5665F), was added to the samples and returned to 4° C.(protected from light) for 30 minutes. Single stain controls wereincluded for use in compensation matrices. Red blood cells were removedby adding 200 μL of lysis buffer and incubating for 10 minutes at roomtemperature while rocking. The plate was then centrifuged at 270×g forthree minutes and supernatant removed. This step was repeated untilsupernatant was clear. 200 μL of FACS buffer was added to each well towash cells, centrifuged as above, resuspended in 80 μL of FACS bufferand read immediately on a digital FACS Canto II HTS (BD Bioscience) flowcytometer. Data was analyzed using FlowJo software (BD Bioscience).Macrophage subpopulations were determined using CD172, CD14, CD16markers and assessed for expression of CD163.

In Vivo Mouse Lung Infection Challenge Model (Murine)

The challenge organism was P. multocida 46572. Target challengeconcentration was 5×10² CFU/mouse. Isolated colonies from overnightgrowth (37° C. with 5% CO₂) on trypticase soy agar (TSA II) blood plateswere transferred to room temperature Brain Heart Infusion Broth (BHIB).The broth culture was incubated 3.5-4 hours to approximately mid-logphase of growth, as measured by forward light scatter at 600 nm (OD600,0.200). The culture was centrifuged to collect the bacterial pellet. Thepellet was re-suspended in BHIB and adjusted to provide an approximateconcentration of 2.7 log¹⁰ colony forming units (CFU) in 0.04 mL at thehighest concentration. The challenge inoculum concentration wasconfirmed by serial dilutions of the inoculum for CFU enumeration. OnDay −5, CD-1 female mice were received. Mice were given standard rodentdiet and water ad libitum. On Day 0, bacterial inoculum (0.04 mL) wasadministered to each mouse (n=36) intranasally. Compounds of theinvention were dosed at 20 mg/kg (0.1 mL) in a buffered (˜pH 5.4)propylene glycol, monothioglycerol and water solution by subcutaneousinjection. Animals were observed from Days 1-10. The study wasterminated on Day 10. In addition, some treatment groups were sampled at6, 24, and 48 hours post bacterial challenge for RNA sequence analysisof lung tissue.

In Vivo Bovine Lung Infection Challenge Model

The challenge organism was M. haemolytica (OSU-012103-BHI). Thechallenge organism was grown in 100 mL of brain heart infusion (BHI)medium in a 250 mL baffled flask and inoculated with 0.1 mL of thawedstock bacterial culture. The culture was incubated overnight (˜15-18hours) at 150 RPM in a 37° C. shaker-incubator. A 2 mL aliquot of theovernight culture was used to inoculate each 100 mL of media in abaffled flask containing fresh BHI medium at a ratio of ˜1/3 broth tototal volume of the flask. The culture was incubated for about 2 to 6hours at 150 RPM at 37° C. When the optical density (OD) at 650 nmreached 0.800 (approximately 1×10⁹ CFU/mL), the culture was chilled inan ice bath. The culture was centrifuged to collect the bacterialpellet. The pellet was re-suspended in a phosphate buffered saline (PBS)to the original absorbance value. The resulting suspension was furtherdiluted to the appropriate challenge concentration. For each challengedose, the appropriate amount of stock culture was added to apre-measured volume of PBS medium to prepare the 120 mL dose. Thedilution was prepared just prior to challenge administration. A 30 mLamount of BHI medium or PBS was infused into the lung immediatelyfollowing administration of the challenge material. Male (or steer)Holstein cattle were received on Day −10. Animals received apre-shipping dose of Advocin© and a) had M. haemolytica leukotoxinantibody titers less than 0.85 S/P ratio prior to allotment, asdetermined by a serological ELISA to leukotoxin of M. haemolytica; b)were negative for persistent BVDV infection as determined by ear notchsampling prior to arrival; c) free from systemic disease or indicationsof being immune-compromised; and d) in good health. Animals were fed anon-antibiotic diet and provided water ad libitum. A pre-challenge groupof animals (N=4/group) received a challenge dose (˜3.3×10⁸ CFU/dose or˜1×10⁹ CFU/dose) and treatment (10 mg/kg) on Day −8 to determine theoptimal challenge dose. The challenge material was administered to thelungs via a plastic cannula subsequent to local lidocaine anesthesia.Treatment dose was administered by subcutaneous injection and thetreatment drug was solubilized in a buffered (˜pH 5-6) compositioncomprising propylene glycol and water. On Day 0, remaining animals(N=24/group) were challenged and then treated with either a 0.2, 0.5,2.5, or 10 mg/kg amount of study compound (100 mg/mL). Animals wereevaluated through the duration of the study which terminated on Day 6for clinical signs of disease. Lungs were swabbed for bacterial presenceand lung lesions were scored based on percent gross lung involvement andrespiratory severity determined.

In Vivo Temporal Study

A clinical and genomics temporal study was conducted to mimic typicalmanagement cattle practices that result in the development of BRD. Thedesign included extensive longitudinal genomics sampling, including theairway, as well as comprehensive clinical evaluation, with the goal oflinking mechanism of disease to clinical phenotype. The study resultedin a 20% incidence of classic BRD as assessed by standard clinicalscoring criteria. To allow data analysis, animals were assigned tophenotypic groups based on clinical signs, lung lesions, and treatmentqualification as per feedlot standards. The study served as theframework to interpret the biological processes that resulted inhealthy, subclinical, and diseased animals at the typical interventionpoint of arrival at the feedlot. For example, comparison of wholetranscriptome RNA sequencing data of naso-pharyngeal swabs collected atthe time analogous to arrival at the feedlot could be aligned with aknown clinical outcome from the study results.

The study demonstrated that contrary to the dogma, there is anupregulation of innate inflammatory pathways prior to shipment and atthe post-shipping feedlot arrival timepoint. This heightenedinflammatory state is seen in virtually all animals despite the finalclinical outcome. Further analysis of the comprehensive data revealedthat animals that progressed to develop BRD continued to have elevatedinnate inflammatory pathway signatures expressed in the airway while thehealthy and subclinical animals (healthy cohort) showed self-moderateddecrease of the inflammatory signals within a couple of days (FIG. 2).

Of significance, is the presence of the unresolved exacerbatedinflammation state at Days 4-6 which results in differential bacterialinvolvement of H. somni and M. haemolytica and the transition to thefull BRD disease complex. Both healthy and diseased cohorts wereconfirmed by RNA sequence analysis to have similar viral and bacterialexposures from Day −1 through Day 4. The healthy cohort (no disease andsubclinical) were able to resolve the inflammation state early, Day 0 orDay 1. The BRD (diseased) cohort did not resolve the inflammation stateand progressed to the full BRD complex. A significant increase oftypical BRD-associated microorganisms (M. bovis, H. somni, and M.haemolytica) was not detectable until after the innate inflammatorypathways failed to resolve at Day 4-6. It is believed that it is theunresolved inflammatory process that enables progression to the full BRDcomplex.

From this temporal study, pathways for intervention were identified.These include Pattern Recognition Receptor (PRR) TLR-4 activation,inflammasome signaling, NF-κB and STAT transcription, which weretargeted to reduce the pathologic innate inflammatory cascade prior todisease onset. Some key inflammatory cytokines included IL-1β, IL-6,IL-36, and TNF-α which were further confirmed through in vitrocell-based assays and ex vivo bovine infection models. The study alsoserved to identify biomarkers correlating with disease severity (CD163,IL-6, IL-36 and haptoglobin).

Plasma samples were collected from at-risk calves upon arrival at afeedlot, assessed for cytokine levels. The data was correlated withfinal disease (BRD) as assessed by clinical scoring for seven days. Ofthe cohort, 14 animals were healthy and 24 were diagnosed with BRD. Aspredicted for BRD etiology and pathogenesis, NF-κB mediated cytokines,including IL-6, were highest in animals that would develop clinical BRD.Interestingly, there was a correlation between higher levels of IFN-γ inanimals at arrival associated with animals that did not progress toclinical BRD (FIG. 3). This data further supports that calves withheightened levels of some pro-inflammatory cytokines (IL-6 and IL-8) onarrival to the feedlot are associated with poor clinical outcome whereascalves that have increased IFN-γ, a cytokine associated with pathogenclearance, are associated with remaining healthy and not progressing toBRD.

In-Vitro Studies

The compounds of the invention had MIC values for multiple BRDpathogenic bacterial strains of M. haemolytica and P. multocida and fromother pathogenic bacterial strains including E. coli, S. aureus, and E.faecalis that were considered to be non-antibacterial (i.e., MIC >64μg/mL). Bacterial strains included the following: E. coli (A25922K/T,W3110WT, AG100T, AG100AT); E. faecalis (A19433K/T); M. haemolytica(12726K, 46571 K/T, A33396K/T, 49023T, and others); P. multocida(46572K, 43137K, 34135T, and others); S. aureus (A29213K/T); and H.somni (A7000025K). The K and T represent a specific strain at two studysite locations. For Example, Example H-91 had MIC values that were >256μg/mL in 25 different strains each of M. haemolytica and P. multocida;and an MIC >64 for H. somni (31 strains). Example H-11 had MICvalues >64 for the same M. haemolytica, P. multocida and H. somnistrains. As defined herein, the non-antibacterial compounds had MICvalues >64 μg/mL in the BRD bacterial strains tested. Some compoundsdefined herein were considered to have some antibacterial properties asa result of at least one MIC value ≤64 μg/mL for any one of thebacterial strains tested. Except for a few compounds of the invention,most had MIC values >64 μg/mL for the BRD bacterial strains describedabove, and for the other non-BRD strains as well. The K and T representa specific strain at two different study site locations.

Comparatively, gamithromycin had MIC values ranging from about 0.5-1μg/mL and 1-2 μg/mL for the same M. haemolytica and P. multocida strainsrespectively; and about 0.25-8 μg/mL for the H. somni strains. For thesame H. somni strains, florfenicol and enrofloxacin had MIC's rangingfrom 0.12-2 μg/mL and <0.06-1 μg/mL, respectively; clearly showing theirantibacterial potential against these bacterial strains. In addition,the MIC's (μg/mL) for tulathromycin and M9 for the following bacterialisolates is shown in Table 1.

TABLE 1 Comparative MIC's (μg/mL) for Bacterial Isolates BacterialIsolate Tulathromycin M9 S. aureus ATCC 29213 8 64 E. coli ATCC 259222 >64 E. coli W3110 8 64 M. haemolytica ATCC 33396 1 32 M. haemolytica12726 2 32 M. haemolytica 46571* 1 32 P. multocida ATCC 43137 1 16 P.multocida 46572** 1 8 *Indicates bovine efficacy challenge strain**Indicates murine efficacy challenge strain.

In an Ames mutagenicity test, Example H-91 (1-5000 μg/plate; using theplate incorporation method and a standard panel of bacterial (E. coliand Salmonella isolates) was negative (non-mutagenic).

In summary, Examples H-11 and H-91 demonstrated a lack of in vitroactivity vs. clinically relevant pathogenic strains for BRD (M.haemolytica and P. multocida) and a lack of clinically relevant MICs hasbeen established against all zoonotic bacteria tested to date.Additionally, the compounds were non-mutagenic in Ames testing.

The compounds of the invention share the most commonly describedimmune-effects with the parent macrolide class including modulation ofpro-inflammatory cytokine production and the trafficking/fate ofgranulocytes. Reductions in IL-1β, IL-6, IL-36 and TNFα with thecompounds of the invention have been observed and have consistently beenassociated with a positive clinical outcome. The compounds of theinvention also consistently mitigate the increase in biomarkers IL-6,IL-36, CD163 and haptoglobin which have also been associated withclinical disease outcome. Therefore, underlying mechanism of thecompounds of the invention are likely the broad-spectrum modulation ofinnate inflammatory response.

In vitro systems were functional in demonstrating inhibition ofcytokines TNF-α, IL-6 and IL-1β in BRD relevant primary cell typesincluding bovine alveolar macrophages and nasopharyngeal epithelialcells. The effect of multiple cytokines was not easily quantified usingsingle cell types. Therefore, a fresh whole bovine blood assay wasdeveloped with LPS as a stimulant (TLR-4 agonist) and with IL-1β andTNF-α as the read-out. Compounds of the invention were evaluated againsta positive control for their ability to inhibit LPS-induced IL-1β andTNF-α as an overall evaluation of relative potency and modulation oftarget pathways (Table 6).

The second immunomodulation in vitro assay evaluated the potential forphospholipidosis with the compounds of the invention in bovine alveolarmacrophages. This assay is utilized to determine cellular uptake of thecompounds of the invention in relevant bovine and murine cell types.This assay utilized Invitrogen's commercially available HCS LipidToxdetection kit with an Incucyte real time fluorescence reader to observevariations in EC₅₀ and phospholipidosis profiles based on compoundconcentrations. Murine intraperitoneal macrophages were also used in thesame assay to evaluate species variability for potential correlationwith mouse efficacy results. The combination of the bovine whole bloodassay and phospholipidosis assays enabled rank ordering for progressioninto in vivo testing in the murine challenge model.

Transcriptional changes as do not always correlate with protein levelsand observed phenotype. In order to correlate RNA sequencing data tocytokine changes the whole blood assay was utilized. Example H-11downregulated LPS induced pathologic-associated cytokine productionincluding IL-1β, TNF-α and IL-6. The results (Table 2) demonstrate areduction in three cytokines which have been identified to be relevantto BRD disease state. Enhancement (enh), as indicated in Table 2, isobserved in IL-1β cytokine levels when a compound is inhibitory at lowerconcentrations, however, fails to reach an IC₅₀ value. The enhancementresult represents an overall stimulation of cytokine levels due tocellular stress or potential toxicity with increasing concentrations ofthe compound, representing a typical bell shape response curve forimmunomodulatory activity. In addition, LPS stimulated whole bovineblood assays (4 independent studies with multiple blood donors) withExample H-11 showed a dose dependent reduction in the expression of keycytokines (IL-6, TNF-α and IL-1β) associated with BRD (FIG. 4); furthersupporting cytokine inhibition.

TABLE 2 Immunomodulation Assay Results Analog M9 H-11 H-91 TNF-α IC₅₀(μM) 250 8 90 IL-1β IC₅₀ (μM) 250 36* 103* Phospholipidosis EC₅₀ (mM)3.74    0.004    0.088 logP 2.2   3.2   3.1 *enhanced response atconcentration indicating potential cytotoxicity

Further data supporting this hypothesis includes murine studies using aP. multocida infection in mice. For example, M9 and Example H-91 wereclinically efficacious when airway tissues were collected longitudinallyand evaluated for transcriptomic analysis. Using these results, specifictranscriptional expression demonstrated regulators consistent with somekey BRD pathways (PRRs, cytokines, STAT) and cellular cross-talkactivity.

Mouse Murine Study

Compounds of the invention were selected for progression into murineefficacy and beyond based on a significant MIC increase (target >64μg/mL) for all bacterial strains in the screening panel. This assessmentwas combined with an in vitro immunomodulation potency equal to orbetter than M9, TNF-α and IL-1 IC50 of ˜250 μM for both cytokines and anEC₅₀ for phospholipidosis of 3.74 mM.

The murine efficacy model (P. multocida challenge) was optimized, andthe treatment group size was powered to be able to observe statisticallysignificant improvement of survival to expected ranges forimmunomodulatory compounds. The experimental design was a randomizedcomplete block design. Mice were individually identified and treatmentgroups comingled within a cage, with every treatment group equallyrepresented across cages. Mortality was the primary variable. Mortalitydata was analyzed using a generalized mixed model with fixed effect oftreatment and random effect of block. Survival time was also analyzedusing the SAS PHREG (survival analysis) procedure to examine whetherthere were significant differences between treatment groups and thecontrol group. Numerous compounds of the invention and M9 (positivecontrol) were tested in this model at a dose of 20 mg/kg. Typicalpercent survival for no treatment control is in the range of 0-20% basedon study to study variation in challenge inoculum and rate of infection.The analogs tested had an MIC vs. challenge strain at 64 μg/ml comparedto M9 at (8 μg/mL). Mouse survival for M9 was about 90-100%, furthersupporting its antibacterial properties against the bacterial strain(Table 3). Survival values presented are harmonized against thecomparative vehicle survival rate.

TABLE 3 Mouse Murine Percent Survival Ex.# % B-2 28 B-4 7 B-5 <1 B-6 1B-13 48 B-13a 44 H-3 8 H-11 36 H-13 59 H-14 46 H-39 44 H-60 72 H-72 4H-73 4 H-74 11 H-83 11 H-87 14 H-91 38 H-95 39 H-96 11 H-100 19 J-3 25J-4 5 J-7 39

In one murine P. multocida intranasal challenge study, mice wereadministered tulathromycin (16 mg/kg; T02), M9 (32 mg/kg; T03), orceftiofur (9 mg/kg; T04) by subcutaneous injection 18 hours afterbacterial challenge (5×10³ CFU/mouse) for lung tissue RNA sequenceanalysis. Survival at Day 7 was about 80%, 50%, and 90% for T02, T03,and T04, respectively, compared to placebo at 0%. Differential geneexpression from total lung tissue RNA sequence analysis indicated atleast 226 unique genes were up or down regulated (with significance) forT03. Output from ingenuity pathway analysis of these unique genespredicted major upstream regulators of the involved pathways. Data wasanalyzed based on the number of genes being modulated in the samedirection that were associated with a given upstream regulator. Anactivation z-score of 2 or greater is considered significant and thedirection change is indicated by + (activated) or − (inhibited). The top5 pathways included: IL-9 signaling, glucocorticoid receptor signaling,prolactin signaling, JAK STAT signaling, and IL-17 signaling. The top 6upstream regulators (activation z-score) included: lipopolysaccharide(−6.725), TNF (−4.669), IFNG (−5.759), IL-1β (−5.947), STAT1 (−2.787),and poly rl:rC-RNA (−5.289). Even though this study was run in themurine model, the top upstream regulators identified as being modulatedby M9 include an almost ubiquitous overlap with the pathways identifiedin the natural disease study as being key mediators in BRD, andtherefore is modulating highly relevant pathways in BRD pathobiology.

Single cell RNA sequencing was employed using the whole blood assaydescribed above demonstrating drug-induced changes in protein cytokineexpression to further substantiate cell type and pathway modulation bythe compounds of the invention. Whole blood contains a variety of typesof immune cells including both myeloid (e.g., neutrophils andmacrophages) and lymphoid (e.g., T and B cells) derived cells as well asfurther differentiated cell-type specific subsets. Cells withtranscriptional similarities were clustered together and identities wereprojected based on marker reference lists which were cross-checked withtop differentially expressed genes against our established bovineantibody-based marker panels. In the absence of any stimulation,compound H-91 influenced genes that correlated in particular to cellclusters identified as neutrophils/macrophages, monocytes, and T and Blymphocytes. Samples were sequenced at 30 minutes, 4 hours, and 20 hoursstimulation (LPS, as described above) with the relatively largestchanges seen at 20-hours. Among the genes with the largestdifferentially expression values included but were not limited tocytokines such as IL-1β, chemokines such as CXCL2 and CXCL8, andinterferon-stimulated gene (ISG) family members (data not shown).

Focusing on the clusters of cells identified in the drug influencecorrelation, lists of significantly modulated genes (adjusted p <0.05and absolute log(Fold Change) >0.25) were used to identify the predictedupstream regulators of the associated pathways. These regulators include(but are not limited to) components central to hypothesized pathologicalpathways in BRD such as TNFα, LPS (TLR4 agonist), NFκB, IL-1β and IL-6.As described previously, the mitigation of these inflammatory pathwaysthat are increased in BRD correlates with positive clinical outcome. Inthis experimental system, LPS was administered to activate theinflammatory pathways seen in calves at-risk for BRD and fulltranscriptome sequencing was used to determine drug effect on these keypathways. Within the myeloid cell populations, the neutrophil/activatedmacrophage cluster and monocyte cluster, the drug mitigated theactivation of the majority of the inflammatory pathways described above.Within the B lymphocyte populations, the drug mitigated the LPS-inducedactivation within nearly all the top pathways regulators identified.This result makes sense as the PRR associated pathways described hereare consistently expressed between the myeloid cell populations and Bcells (both can serve as professional antigen-presenting cells). T cellsexpress the family of PRRs to a much lesser extent so it follows thatthe pathways targeted by the drug are less affected in this cell type.Interestingly, the group of pathway regulators that were increased bydrug in the context of stimulation (within myeloid and T cell clusters)represent pathways often associated with immunity against viral-typepathogens, interferons and STAT (which is a signaling molecule for theinterferon family). This result expands on the mechanism of actiondescription above where drug mitigates exacerbates innateproinflammatory pathways related to bacterial process pathobiology tomay also upregulate immune defenses to viral pathogens known to be amajor component in BRD.

Given the overlap between immunomodulatory properties of macrolides andthe described target pathways, the des-methyl tulathromycin metabolite,M9, with reduced antimicrobial activity was utilized in a natural bovinerespiratory disease study. The primary clinical endpoint for efficacywas treatment failure/success over a 14-day observation period.Clinically normal beef calves (150-200 kg) at moderate risk for BRD weredosed on arrival to the feedlot. Animals (N=114/group) received saline(T01), 5 mg/kg M9 (T02), 10 mg/kg M9 (T03) or Zactran (T04). Percentfailure was 43%, 19.3%, 8.8%, and 29.8% for the T01, T02, T03, and T04groups, respectively. Bacterial isolates were collected at necropsy andMICs were evaluated (Table 4). In a separate PK study, the maximumplasma concentration following a 10 mg/kg dose was 5 μg/mL. Based on theMICs observed (Table 4) and the maximum plasma concentration it waspostulated that the residual MIC activity of M9 was not responsible forthe significant overall outcome and the efficacy was primarily due tothe immunomodulatory effects of M9. M9 demonstrated efficacy in anatural BRD infection study with statistical superiority demonstratedover untreated control groups in the reduction of lung lesions andtreatment failure (attitude, rectal temperature, and respiratoryrate/effort and nasal/ocular discharge). However, as can be seen forsome of the BRD bacterial isolates, M9 has antibacterial (i.e., MIC <64μg/mL) properties.

TABLE 4 MIC of Recovered Isolates: Natural Bovine Respiratory DiseaseStudy Lung Bacteria Isolated at Necropsy M9 gamithromycin (Zactran)MIC50 MIC90 Range MIC50 MIC90 Range Bacteria (n) (μg/mL) (μg/mL) (μg/mL)(μg/mL) (μg/mL) (μg/mL) M. haemolytica (116) >64 >64 32->64 1 >640.5->64 P. multocida (33) 16 >64  8->64 1 >64 0.5->64 H. somni (25) 3232 8-64 0.25 2 0.12-2   

In a separate natural field study, using a compound of the invention(Example H-91), crossbred cattle (bulls, steers, heifers) ranging in agefrom 5 months or older weighing 300-500 pounds were used. Animals werepenned and fed a non-antibiotic diet and provided water ad libitum.Animals (N=114/group) received a single saline placebo (T01) ortreatment dose of Example H-91 at 0.5 mg/kg (T02) or 2.5 mg/kg H-91(T03) on Day 0 by subcutaneous injection. The compound (20 mg/mL) wassolubilized in a buffered (˜pH 5-6) solution comprising propylene glycoland water. The study also included an active control group (N=57)wherein each animal received a labeled dose of Zuprevo (tildipirosin, 4mg/kg, T04). A separate group of animals (N=3) received either the 0.5mg/kg or 2.5 mg/kg dose of Example H-91 on Day 2. Animals were observedand clinically monitored (e.g., plasma, rectal temperature, attitude,respiratory (rate/effort and nasal/ocular discharge) until studytermination on Day 7 to evaluate BRD. Bacterial swabs were also takenfrom cattle (treatment failures and lung lesions) and submitted forculture and isolation of M. haemolytica, P. multocida, H. somni, and M.bovis. Treatment success was 43.0% (T01), 57.9% (T02), 43.9% (T03), and86.0% (T04). In view of the data presented, lower doses of a compound ofthe invention may be required for mitigating the innate immune andinflammatory response in the target animal. This correlates well withthe in vitro assay data indicating at high concentration the immuneresponse in cells is often increased as observed for IL-1β.

In another natural field study, crossbred cattle (bulls, steers,heifers) ranging in age from 5 months or older weighing 300-500 poundswere used. Animals were penned and fed a non-antibiotic diet andprovided water ad libitum. Animals (N=84/group) received a singletreatment of Example H-11 at 0.03 mg/kg (T02), 0.1 mg/kg (T03), 0.3mg/kg (T04), 1 mg/kg (T05), or 0.05 ml/kg saline (T01). A subset of 42animals received a single 4 mg/kg dose of Zuprevo (T06; 180 mg/mL).Animals in the T01-T06 groups received the dose on Day 0. Route ofadministration for all treatment groups was by subcutaneous injection.Actives were solubilized in a buffered (˜ pH 5-6) solution comprisingpropylene glycol and water to prepare 1.2 mg/mL (T02), 4 mg/mL (T03), 12mg/mL (T04), and 40 mg/mL (T05). Animals were observed and clinicallymonitored (e.g., plasma, rectal temperature, attitude, respiratory(rate/effort and nasal/ocular discharge) until study termination on Day7 to evaluate BRD. Bacterial swabs were also taken from cattle(treatment failures and lung lesions) and submitted for culture andisolation of M. haemolytica, P. multocida, H. somni, and M. bovis.Treatment success was 32.1% (T01), 58.3% (T02), 60.7% (T03), 51.2%(T04), 40.5% (T05) and 85.7% (T06). Compared to T01, T02 (0.0008), T03(0.0003), T04 (0.0133), and T06 (<0.0001) were statistically significantat the 0.20 level.

Intensive sample collection was conducted over a 96-hour period in asubset of cattle treated with Example H-91 (0.5 mg/kg) or H-11 (0.1mg/kg) in the natural bovine infection studies. These compoundsdemonstrated a rapid and transient increase in IL-36RA that increased toabout 275% for Example H-91 and about 50% for Example H-11, compared tobaseline, within 1 hour (FIG. 5). IL-36RA remained elevated for roughly8 hours and then the concentrations dropped to −55% of the baselineconcentration. A dose dependent reduction was observed from 48-96 hours.The compounds of the invention have shown an up-regulation of IL-36RA,which then binds to IL-36R limiting the pro-inflammatory response ofIL-36. In addition, the IL-8 levels from one of the natural infectionstudies with Example H-91, increased 270% over the course of the studyfor control animals. In contrast, the IL-8 levels in animals dosed withExample H-91 decreased by about 15%.

To evaluate immunomodulation effects and potential biomarkers, a bovineM. haemolytica (strain: OSU-012103-BHI) intratracheal lung challengemodel study was completed utilizing M9 treatment in the presence andabsence of bacterial challenge and a Draxxin© comparator. It isimportant to note that the MIC for M9 to the challenge strain is >64μg/mL indicating the effects observed were primarily throughimmunomodulation and not reduction of the bacterial challenge. Animalswere administered 0.05 mL/kg saline (T01), 10 mg/kg M9 (T02); Draxxin2.5 mg/kg (T03) and 10 mg/kg M9 (T04) by subcutaneous injection on Day−1. Dose was based on body weight. Animals were challenge on Day 0 withthe exception of T04. Blood was collected longitudinally throughout thestudy for biomarker evaluation panel (e.g., IL-6 and CD163) includingtwo baseline samples prior to treatment. Study results are presented inTable 5 and in FIG. 6. FIG. 6A depicts the area under the curveconcentrations for IL-6 protein for individual animals against percentlung lesion scores and FIG. 6B depicts the CD163 fold change area underthe curve for individual animals against percent lung lesion scores.Data is represented as percent lung lesion scores against the area underthe curve (AUC) for IL-6 protein (immunoassay expressed in pg/mL) andCD163 (flow cytometric mean fluorescent intensity (MFI) in fold changefrom baseline). In both assays, a 2-fold change is typically consideredto be relevant.

TABLE 5 M9 Intratracheal Lung Challenge Study Treatment No. GroupChallenge Animals Mortality T01 M. haemolytica 6 4/6 T02 6 1/6 T03 6 0/6T04 No challenge 6 0/6

IL-6 was elevated and was correlated with higher rectal temperature(data not presented) and mortality. M9 and Draxxin© significantlyreduced IL-6 levels which also correlated with overall animal survivalor disease progression. CD163 mRNA expression followed the initialinnate inflammatory cascade signaling in animals that showed clinicalsigns of BRD within a few days. The increased expression of CD163 onmacrophages correlates to clinical disease progression in longitudinalsampling of whole blood. M9 mitigates the pathologic increase in CD163expression.

In summary, M9 demonstrated statistically significant efficacy in both anatural BRD infection as compared to saline (T01) in the M. haemolyticachallenge model. In a separate study, 10 mg/kg of M9 demonstratedstatistical superiority versus saline control in reduction of lunglesions (20% vs. 31%, p=0.023) and mortality (13% vs. 38.9%, p=0.025).Additionally, reduction of biomarkers consistent with the proposedmechanism were observed. However, the residual antibacterial activity ofM9 (MIC's≤64 μg/mL) against target pathogens was not in line with thenon-antibiotic immunomodulator profile (>64 μg/mL).

In a separate bovine M. haemolytica intratracheal lung challenge study,Example H-91 was administered 24 hours prior to bacterial challengeconsistent with the on-arrival control/prevention product profile. Thestudy was designed to also include an assessment of immunomodulationbiomarkers. Animals (n=24/group) received a subcutaneous dose of saline(0.05 mL/kg; T01); 0.5 mg/kg (T02) or 2.5 mg/kg (T03; n=23) of ExampleH-91; or a 10 mg/kg (T04) of M9. Dose amount was based on body weight.On Day 0, animals were challenged with M. haemolytica. T01-T04 animalswere evaluated for clinical scores, lung lesions and mortality to assessstatistical success. Outcomes included: respiratory severity score0=normal, 1=mild clinical signs, 2=acute BRD clinical disease, 3=severeBRD clinical disease; attitude score 0=normal, 1=mild depression,2=moderate to marked depression, 3=moribund. A treatment failure wasconsidered if: a) the clinical score was 3 or b) a combination of scoresof 2+2 with a rectal temperature of >104° F. Daily clinical scores wereobserved on a scale of 0-3; including attitude and respiratory, withrectal temperatures. Lung lesions were assessed at necropsy. On Day 6,the study was terminated and all remaining animals were euthanized. Ananimal will be described as surviving (euthanized due to end of study;no) or mortality/euthanized (euthanized or died prior to schedulednecropsy due to challenge; yes) based on data collected on the finaldisposition form and summarized by treatment. Tables 6 and 7, and FIG. 7summarize the study results of this intratracheal study. FIG. 7A depictsthe area under the curve concentrations for IL-6 protein for individualanimals against percent lung lesion scores and FIG. 7B depicts the 00163fold change area under the curve for individual animals against percentlung lesion scores, by flow cytometric analysis depicting the meanfluorescent intensity expressed as a fold change from baseline (>2 isconsidered biologically relevant).

TABLE 6 Intratracheal Lung Study - Lung Lesion Scoring For Example H-91Back Standard Transform Error % Lower 80% Upper 80% Range % LS % LungConfidence Confidence Lung Significance Lung with with Limit of Limit ofwith at .20 level Lesions Lesions Mean Mean Lesions P value to T01 T0121 5 15 29 0 to 71 T02 8 3 5 12 0 to 39 0.0027 Yes T03 9 3 6 13 0 to 580.0057 Yes T04 12 4 7 19 0 to 76 0.1244 Yes

As can be observed from Table 6, statistical significance (p:50.2) wasestablished for Example H-91 for T02 and T03, as well as for thepositive control group, T04; when compared to T01.

TABLE 7 Intratracheal Study - Mortality for Example H-91Mortality/Euthanization (Yes/No) Total No Yes Observations SignificanceNumber % Number % Number p-value to T01 T01 16 66.7 8 33.3 24 NA NA T0223 100 0 0 23 0.0039 Yes T03 22 91.7 2 8.3 24 0.0723 Yes T04 21 87.5 312.5 24 0.1681 YesAs can be observed from Table 7, statistical significance (p:0.2)demonstrated in mortality as compared to no treatment saline control forExample H-91 for T02 and T03 as well as for the positive control group,T04; when compared to T01.

Data presented in FIG. 7 is represented as percent lung lesion scoresagainst the area under the curve (AUC) for IL-6 protein (immunoassayexpressed in pg/mL) and CD163 (flow cytometric mean fluorescentintensity (MFI) in fold change from baseline). In both assays, a 2-foldchange is typically considered to be relevant.

Overall, the M. haemolytica intratracheal challenge study demonstratedefficacy for Example H-91 at 0.5 mg/kg and 2.5 mg/kg doses, administeredsubcutaneously. The compound demonstrated an MIC of >256 μg/mL againstthe M haemolytica challenge strain. Additionally, an MIC of >256 μg/mLwas also established against all M. haemolytica target pathogens tested.Following a 2.5 mg/kg dose the H-91 plasma maximum concentration (Cmax)was 152 ng/mL. The efficacy generated by Example H-91 at both 0.5 mg/kgand 2.5 mg/kg doses is due to its activity as an immunomodulator and notas an antibiotic. Biomarker analysis demonstrated reduction in IL-6 andCD163 consistent with dose and clinical outcome. The biomarkerassessment supports the proposed mechanism of immunomodulation.

In a separate M. haemolytica bovine intratracheal lung challenge studywith a similar design as above, Example H-11 was assessed. Example H-11was dosed at 0.5 mg/kg (T03) and 2.5 mg/kg (T04); saline placebo(negative control, T01) and M9 (positive control, 10 mg/kg, T05) werealso assessed. Doses were administered to the animals by subcutaneousinjection 24 hours prior to bacterial challenge. Lung lesion andmortality data is shown in Tables 8 and 9, respectively. Neutrophilcounts, IL-6 and CD163 data is shown in FIG. 8. There was a 43% (medianvalue) reduction in IL-6 levels at 32 hours post challenge while thegeometric mean demonstrated a 51% reduction in IL-6 levels. Drugtreatment at 24 hours prior to challenge reduced the number of bloodneutrophils, plasma IL-6 and expression of scavenger receptor CD163 onblood macrophages; all of which correspond to clinical outcome

TABLE 8 Intratracheal Lung Study - Lung Lesion Scoring: Examples H-11Back Standard Transform Error % Lower 80% Upper 80% Range % LS % LungConfidence Confidence Lung Significance Lung with with Limit of Limit ofwith at .20 level Lesions Lesions Mean Mean Lesions P value to T01 T0133 7 23 44 2 to 75 T03 28 7 18 38 0 to 68 0.381 No (H-11) T04 21 6 13 312 to 70 0.0373 Yes (H-11) T05 24 7 15 35 1 to 70 0.1481 yes

As can be observed from Table 8, statistical significance (p:50.2) wasestablished for Example H-11 (T04); as well as for the positive controlgroup, T05; when compared to T01.

TABLE 9 Intratracheal Study - Mortality for Examples H-11Mortality/Euthanization (Yes/No) Total No Yes Observations SignificanceNumber % Number % Number p-value to T01 T01 15 62.5 9 37.5 24 NA T03 2083.3 4 16.7 24 0.1028 Yes T04 18 75.0 6 25.0 24 0.3363 No T05 20 87.0 313.0 23 0.0652 YesAs can be observed from Table 9, statistical significance (p:50.2)demonstrated in mortality as compared to no treatment saline control forExample H-11 (T03) as well as for the positive control group (T05); whencompared to T01.

As previously demonstrated, M9 and Example H-11 and H-91 downregulatedexacerbated plasma IL-6 and CD163 (two independent studies). Asdescribed, CD163 is an acute phase protein receptor expressed onactivated monocytes in the peripheral blood and macrophages in tissuethat binds haptoglobin and hemoglobin to limit oxidative inflammation inthe tissue. During chronic inflammatory diseases, expression of CD163 isincreased and we see that same expression pattern in the M. haemolyticachallenge model and in natural disease BRD. These data pointed todrug-mediated reduction in biomarkers of inflammatory pathways. Thisdownregulation of these biomarkers was associated with a positiveclinical outcome in naturally occurring BRD.

Lymphocyte populations were also assessed in a separate in vivo genomicschallenge model conducted to further elucidate the drugs mechanism ofaction. Animals (n=8/group; Holstein, 4-5 months old) were administeredplacebo (saline, T01), a 0.1 mg/kg dose of H-11 (T02) or a 2.5 mg/kgH-11 (T03) solution dose by subcutaneous injection 24 hours before M.haemolytica intratracheal challenge. As a genomics study, animals werenot allowed to progree to final disease state; as such animals(n=4/group) were necropsied at 24 and 48 hours post challenge. As partof the study, biomarker and genomics time-course sampling was conducted.T cell surface markers included cytotoxic (CD8+) T cells, γδ-T cells andNK cells, with the most noted effects seen in the T helper cells.Cytokine production in T helper subtypes was assessed usingintracellular staining which enables the identification of the specificcell type which is producing the cytokine. Drug treatment resulted in ashift in the balance between T helper type 1 (Th1) and type 17 (Th17) asassessed by production of IFN-γ and IL-17 (IL-17A, specifically),respectively. FIG. 9 shows the intracellular flow cytometriccharacterization of CD4+T helper cell subtype in the blood of animals at24 and 48 hours post treatment with H-11 at 0.1 mg/kg (T02). T helpercells were identified by double expression of CD3 and CD4 while negativefor CD8 with Th17 cells characterized by IL-17 expression and Th1characterized by IFN-γ expression. The increase in Th1:Th17 ratiopost-treatment suggests a functional shift consistent with promotion ofmore productive pathogen-fighting type immunity (Th1) over a responsethat has been associated with pathologic inflammatory responses (Th17)in BRD that is consistent with the role of IL-17-producing T helpercells in the recruitment and activation of neutrophils to affectedtissue sites. The shift described in FIG. 9 with intracellular stainingwas subtle in scale but consistent with treatment-related decreases inIL-17 (IL-17A, specifically) observed in the bronchial alveolar lavage(BAL) fluid and affected consolidated lung tissue collected at necropsy(FIG. 10). FIG. 10 demonstrates the reduction of IL-17 levels asmeasured in the airway of animals challenged with M. haemolytica as aresult of H-11 treatment. The noted absence of IL-17 in healthy lungtissue supports the relevance of the subtle protein changes. Inaddition, these results are consistent with transitional analyses fromthe airways of at-risk calves in the previously described investigativenatural disease study where IL-17 expression levels correlated with poorclinical outcome. Given what is known regarding the pathobiology of BRDand the role of T helper lymphocyte populations in having significantinfluence on the type and/or direction of an inflammatory response, theshift away from Th17 suggests not only a way by which pathologicinflammation in BRD is being controlled, but potentially also suggests amechanism by which treatment may enhance a more productive Th1 responsewhich may promote pathogen clearance.

The data presented herein supports the immunomodulatory (non-antibiotic)effect of the compounds of the invention in that a) all animals in theinvestigative study demonstrated a heightened inflammatory state uponarrival at the feedlot as shown by elevated genomic signatures for PRRs,TLR4, IL-1β, TNF-α and JAK/STAT pathways; b) through genomic analysis itwas confirmed that all animals were exposed to similar pathogensthroughout the course of the study; c) it is the natural ability of thehost to reduce this inflammatory state that predicates the animal forprogression to the full BRD complex; d) reduction of this inflammatorystate establishes a point of intervention for the use of animmunomodulator (compound of the invention); e) the immunomodulationeffects seen with macrolides are consistent with the interventionrequired to combat the excessive innate immune inflammatory responses inthe target animals and progression to BRD; and (f) use of M9 (antibioticactivity) had shown reduced MIC activity to target pathogens. Additionalimmunological marker data obtained from the in vitro immunologicalmodels is shown in Table 10. Compounds resulting in a “>” value for animmunological marker suggests that there was some inherent model effectthat occurred such that an IC₅₀ and/or OS result could not be determinedaccurately.

TABLE 10 Immunological Data for the Urea's of Formula (1) IL-1β IL-1β OSOS TNF-α of LPS IL-6 TNF-α of LPS IL-6 Ex # (IC₅₀ μM) (μM) (IC₅₀ μM) Ex# (IC₅₀ μM) (μM) (IC₅₀ μM) M9 250 na >250 H-56 79 18 6 A-5 >250 24 >250H-58 >250 >250 >250 A-8 >250 101 16 H-59 9 16 30 A-13 200 >500 >500 H-605 3 7 A-22 >250 100 246 H-62 1 <1 1 B-1 25 40 31 H-64 28 16 28 B-1a 3240 — H-65 9 2 6 B-2 11 40 52 H-66 106 250 >250 B-2a 9 16 23 H-69 14 6 8B-3 37 40 65 H-70 13 6 4 B-3a 12 16 26 H-71 32 16 35 B-4 45 80 —H-72 >500 >500 >500 B-6 12 40 41 H-73 >500 >500 — B-7 156 100 143 H-74~600 >500 >500 B-8 2 6 8 H-76 179 100 >500 B-9 107 28 116 H-77 30 200 —B-13 14 16 51 H-81 >250 39 47 B-13a 20 16 — H-83 350 80 — C-2 200 100100 H-87 100 500 — D-2 20 16 30 H-88 56 13 92 E-2 40 40 35 H-91 85 130181 E-154 5 1 4 H-95 10 13 — E-155 8 6 8 H-100 6 16 10 F-2 11 40 30H-102 8 8 11 G-2 80 100 70 H-103 5 3 4 H-3 400 >500 — I-3 40 32 — H-8 61 5 I-7 8 6 16 H-11 8 32 22 J-1 70 200 250 H-13 12 6 9J-2 >500 >500 >500 H-18 24 40 165 J-3 200 200 225 H-19 70 100 181 J-4 71 3 H-20 31 6 >500 J-5 >500 >500 >500 H-22 >500 >500 >500 J-6225 >500 >500 H-23 — 100 193 J-7 200 200 >500 H-24 23 16 30J-8 >500 >500 >500 H-25 19 16 22 J-9 >500 >500 >500 H-26 30 250 >250J-10 20 40 45 H-27 8 16 17 J-12 34 22 126 H-28 13 17 8 J-15 14 16 28H-29 50 3 50 J-16 60 40 — H-30 250 250 >250 J-17 14 40 25 H-31 41 81 41J-18 16 >250 17 H-32 11 44 8 J-19 19 16 — H-33 37 6 57 J-20 7 3 9 H-37 840 12 J-21 65 20 75 H-38 49 >250 36 J-24 31 100 99 H-39 21 6 19 J-25 616 — H-40 45 40 — J-26 122 100 >250 H-42 — 100 177 J-27 48 250 124 H-4334 16 29 J-28 57 100 152 H-45 109 250 130 J-29 19 40 56 H-46 >250 100 —J-30 16 40 111 H-50 >250 >250 >250 J-32 >500 >500 >500 H-51 26 40 52J-33 20 80 85 H-54 9 6 — J-34 40 32 65

The results presented in Table 10 demonstrate a significant increase ininhibition of TNFα, IL-1β, and/or IL-6 for those Formula (1) compoundstested; compared to M9 at similar drug concentrations (250 μM). For M9,the top dose of 500 μM was not high enough to determine anoverstimulation of IL-1β which was recorded as not applicable (n/a).Further data supporting this hypothesis includes murine studies using aP. multocida infection in mice. For example, M9 was clinicallyefficacious when airway tissues were collected longitudinally andevaluated for transcriptomic analysis. Example H-11 and H-91 were alsoconsidered to be clinically efficacious. Using these results, specifictranscriptional expression demonstrated regulators consistent with somekey BRD pathways (PRRs, cytokines, STAT) and cellular cross-talkactivity were assessed.

TNFα is a cell signaling protein, cytokine, that plays a key role insystemic inflammation when produced in excessive upregulated amounts. Inthe bovine whole blood in vitro screening assay the inhibition of TNFαas induced by stimulation by lipopolysaccharide (LPS) and as measured byhalf the maximal inhibitory concentration (IC₅₀) is recognized as theprimary biomarker of immunomodulation potency upon pretreatment with thecompounds of the invention. IL-1β is a mediator of the inflammationresponse and is involved in a number of cellular activities includingproliferation, differentiation and apoptosis. IL-1β is also releasedupon cellular stress or cytotoxicity or upon TLR stimulation. In thebovine whole blood assay the stimulation of IL-1β release uponincreasing concentration of test compound is seen as a potentialcellular toxicity signal as induced by the test compound. In order toestimate a therapeutic index from the in vitro assay a differentialbetween the TNFα IC₅₀ (immunomodulation potency) versus the perceivedcellular toxicity concentration (IL-1β release or overstimulation) wasutilized. Therefore, we propose for a compound to be efficacious invivo, a therapeutic index of >2 (IL-1β overstimulation/TNFα IC₅₀) isrequired, with higher indices predicting a greater potential for anefficacious dose in vivo. A lower TNFα IC₅₀ would indicate a loweroverall mg/kg dose in vivo, assuming a sufficient therapeutic indexof >2. As the in vitro assay index approaches 1 it is proposed that thebalance between immunomodulation and cytotoxicity would be too narrow inorder to achieve an efficacious dose in vivo.

Drug Binding Partners as Potential Biological Targets

The data provided herein relative to the immunological mechanisticactivity of the compounds of the invention is consistent with thepathways presented herein that have been discovered to be important inthe pathobiology of BRD. Key pathways associated with the onset ofnaturally occurring disease include NFκ, TLR4 (often represented by itsagonist such as LPS), JAJ-STAT, TNFα and IL-1β. Downstream signaling ofthese pathways lead to induction of pro-inflammatory cytokines such asTNFα and IL-1β, and IL-6 and chemokines such as CXCL8. These samepathways and their respective components are modulated both in vitro andin vivo by these compounds. Additionally, the types of cells known to beinvolved in these pathways including macrophages, neutrophils andlymphocytes have been used via a whole blood LPS stimulation format(both in vitro and ex vivo) to demonstrate drug-induced changes in geneexpression, cytokine expression, and cell surface receptor activation.In addition to classical immune cells, tissue-resident epithelial andendothelial cells can express innate immune receptors and activate thecanonical pathway.

To further characterize the direct activity of the compounds of theinvention, experiments to identify the drug's direct binding hostpartners(s) were performed with the aim of identifying the potentialbiological targets. Bovine primary cells (peripheral blood mononuclearcells [PBMCs] and polymorphonuclear cells [PMN/neutrophils]) and tissue(trachea, lung) protein homogenates were mixed with M9 and themacrolide, gamithromicin as a comparator. Tissue interactions wereallowed to form using a heterogeneous assembly method (nematic proteinorganization technique, NPOT; Inoviem Scientific); and traditionalwestern blots to identify native-structure proteins bound to thecompound. Mass spectrometry analysis identified eight proteins involvedin the interaction with M9 as compared to gamithromycin. Theantibacterial macrolide gamithromycin was used as a comparator todifferentiate specific binding to M9. These proteins were considered tobe either direct binding partners of the drug or closely involved in thedrug:target interaction (Table 11).

In order to add further clarity to binding partner identification,surface plasma resonance (SPR) technology was used. LCN2 and SLAMF9 wasidentified as direct binding targets at pH levels consistent withmyeloid cell intracellular compartments and diseased tissue sites inBRD. These targets were unique to this drug class compared togamithromycin, a macrolide antibiotic used in the treatment of BRD. Bothtargets fit the paradigm that the immunological mechanism of action islinked to the pathways that are both of key importance as beingdysregulated in BRD and modulated by M9. LCN2 is expressed byneutrophils upon activation of toll-like receptors (TLRs) and is acomponent of the innate inflammatory response. Binding of drug to LCNsuggests a direct interaction with and effect on neutrophils. Verylittle information exists to date on SLAMF9. It is a member of a familyof signal adaptor proteins that is thought to lack signal transductioncapabilities. Very recent studies have demonstrated that SLAMF9 canmodulate the LPS-induced TNF response of macrophages and influencecellular functions. This finding is highly consistent with theimmunological effects that have been demonstrated with the compounds ofthe invention further demonstrating the interplay with key innateinflammatory pathways.

TABLE 11 Drug/Protein Binding Partner Identification Target DescriptionTissue Interaction KD (M) LCN2 Lipocalin 2 or neutrophil PMNs, pH 6.5:4.21E−03 gelatinase-associated Trachea pH 5.5: 4.35E−04 lipocalin SLAMF9Signaling lymphocyte PBMCs, pH 6.5: 2.15E−03 activation molecule 9Trachea pH 5.5: 6.33E−03 NLRX1 Nod-like receptor X1 PBMCs Indirect LPOLactoperoxidase Trachea, Indirect PBMCs, PMNs TLR4 Toll-like receptor 4PBMCs, Indirect Trachea

KD is the equilibrium dissociation constant that was used to present thedrug/target affinity. The identified targets associated with drug weremeasured by surface plasmon resonance (SPR) to define the KD. As can beseen in the table, there was good drug/target binding for LCN2 andSLAMF9 at a biologically relevant pH; while binding for NLRX1, LPO, andTLR4 was indirect.

We claim:
 1. A Formula (1) compound

wherein W is H or Formula (A)

wherein X is —R^(a), —R^(c)NR⁵R⁶, —R^(c)OR⁷, —R^(c)SR⁷, —R^(c)N₃,—R^(c)CN or —R^(c)X′; X is F, Cl, I or Br; R is H, C₁-C₃alkyl,—C(O)NR^(a)R^(d) or —C(O)OR⁸; R^(a), R^(b), R⁰ and R¹ are eachindependently H or C₁-C₆alkyl; or R¹ is benzyl optionally substitutedwith at least one R⁹ substituent; or R¹ is —CH₂Het wherein Het is a 5-6membered heteroaryl ring containing at least one heteroatom selectedfrom N, S and O; and wherein the heteroaryl ring is optionallysubstituted with at least one R⁹ substituent; R^(c) is C₁-C₄alkyl; R^(d)is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, or phenyl optionally substituted withC₁-C₃alkyl, C₁-C₃alkoxy, halogen, cyano, hydroxy, amino, —NHCH₃,—N(CH₃)₂, C₁-C₃haloalkyl or C₁-C₃haloalkoxy; R² and R³ are eachindependently is H, C₁-C₆alkyl, R^(c)NR^(a)R^(b),C₀-C₃alkylC₃-C₆cycloalkyl, C₀-C₃alkylaryl, C₀-C₃alkylheterocycle whereinthe heterocycle is a 5-6 membered saturated or partially saturatedheterocycle ring; or C₀-C₃alkylheteroaryl wherein the heteroaryl is a5-6 membered heteroaryl ring; wherein the heterocycle ring and theheteroaryl ring each contain at least one heteroatom selected from N, Oand S; and wherein the cycloalkyl, aryl, heterocyclic and heteroarylrings are each optionally substituted with at least one R⁹ substituent;or R² and R³ taken together with the nitrogen atom to which they areattached form Ring A, a 4-8 membered heterocyclic ring or a 5-memberedheteroaryl ring, each optionally containing at least one additionalheteroatom selected from N, O and S; each ring is optionally substitutedwith at least one R¹⁰ substituent; and wherein each ring is optionallyfused with Y; R⁵ and R⁶ are each independently selected from H;C₁-C₆alkyl or C₁-C₆alkoxy each optionally substituted with at least onehydroxy; or cyano, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —C(O)R⁸,—C(O)NR^(a)R⁸, —C(O)R^(c)NR^(a)R^(b), —C(O)OR^(c)R⁸, —C(O)ONR^(a)R^(b),—R^(c)NR^(a)C(O)R⁸, —R^(c)C(O)OH, —R^(c)C(O)NR^(a)R^(b),—R^(c)NR^(a)C(O)H, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸, —S(O)_(p)R⁸NR^(a)R^(b), —R^(c)S(O)_(p)NR^(a)R^(b) or—R^(c)NR^(a)S(O)_(p)R⁸; or C₀-C₄alkylaryl, C₀-C₄alkylC₃-C₆cycloalkyl,C₀-C₄alkylheterocycle or C₀-C₄alkylheteroaryl, wherein the heterocycleand heteroaryl rings are each a 5-6 membered monocyclic ring or a 9-10membered fused ring, each containing at least one heteroatom selectedfrom the group consisting of N, O and S; and wherein the aryl,cycloalkyl, heterocycle and heteroaryl rings are optionally substitutedwith at least one R¹⁰ substituent; or R⁵ and R⁶ taken together with thenitrogen atom to which they are attached form Ring B, a 4-8 memberedheterocyclic ring or a 5 membered heteroaryl ring, each optionallycontaining at least one additional heteroatom selected from N, O and S;each ring is optionally substituted with at least one R⁹ substituent;and wherein each ring is optionally fused with Y; R⁷ is H, C₁-C₆alkyl,—R^(c)NR^(a)R^(b), —R^(c)OR^(a), —R^(c)S(O)_(p)R^(a),—R^(c)NR^(a)C(O)R^(b), —R^(c)C(O)NR^(a)R^(b),—R^(c)NR^(a)C(O)NR^(a)R^(b) or —R^(c)NR^(a)C(O)OR^(b); R⁸ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₀-C₄alkylC₃-C₆cycloalkyl, —NR^(a)R^(b), phenyl, a 5-6membered heterocyclic ring containing at least one heteroatom selectedfrom N, O and S, or a 5-6 membered heteroaryl ring containing at leastone heteroatom selected from N, O, and S; and wherein the cycloalkyl,phenyl, heterocycle and heteroaryl are each optionally substituted withat least one substituent selected from C₁-C₄alkyl, halogen, C₁-C₄alkoxy,C₁-C₄haloalkyl and C₁-C₄haloalkoxy; R⁹ is independently selected fromthe group consisting of C₁-C₆alkyl, C₁-C₆alkoxy,C₀-C₄alkylC₃-C₆cycloalkyl, halogen, oxo, hydroxy, cyano, —NR^(a)R^(b),C₁-C₆haloalkyl, C₁-C₆haloalkoxy, —S(O)_(p)R⁸, phenyl, and a 5-6 memberedmonocyclic heterocyclic or heteroaryl ring each containing at least oneheteroatom selected from the group consisting of N, O and S; R¹⁰ isindependently selected from the group consisting of C₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₀-C₄alkylC₃-C₆cycloalkyl,halogen, —NR^(a)R^(b), —S(O)_(p)R⁸, nitro, oxo, cyano, —C(O)H, —C(O)R⁸,—C(O)OR^(a), —OC(O)OR^(a), —NHR^(c)C(O)R^(a), —C(O)NR^(a)R^(b), hydroxy,a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 9-10membered fused heteroaryl ring wherein each heterocyclic and heteroarylring each contain at least one heteroatom selected from the groupconsisting of N, O and S; and phenyl; and wherein the phenyl,heterocyclic and heteroaryl ring are each optionally substituted with atleast one R⁹ substituent; Y is phenyl, pyridinyl, pyrimidyl, pyrazolyl,thienyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, oxazolyl,oxadiazolyl, imidazolyl, furanyl, indolyl, benzothienyl or naphthyl; andp is the integer 0, 1, or 2; stereoisomers thereof, and pharmaceuticallyacceptable salts thereof.
 2. A compound of Formula (1) of claim 1,wherein W is the Formula (A) compound selected from the group consistingof Formula (A0), Formula (A1), Formula (A2), Formula (A3), Formula (A4),Formula (A5), or Formula (A6)

wherein R is H; stereoisomers thereof, and pharmaceutically acceptablesalts thereof.
 3. A Formula (1) compound of claim 2 that is a Formula(1-A1) compound

wherein R^(a), R^(b) and R^(c) are each independently H, methyl, ethylor propyl; R^(c) is methyl, ethyl or propyl; R¹ is methyl, ethyl,propyl, isopropyl; or R¹ is benzyl, —CH₂pyridine, —CH₂pyrimidine,—CH₂pyrazole or —CH₂imidazole, each optionally substituted with at leastone R⁹ substituent selected from methyl, ethyl, methoxy, ethoxy, F, Cl,hydroxy, —CF₃ and —OCF₃; R² and R³ are each independently H, C₁-C₆alkyl;—CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or cyclopropyl, C₁cyclopropyl, cyclobutyl,C₁cyclobutyl, cyclopentyl, C₁cyclopentyl, cyclohexyl, C₁cyclohexyl,phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, C₂piperadinyl,piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl, pyrazolyl,triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each ofwhich is optionally substituted with at least one R⁹ substituentselected from the group consisting of methyl, ethyl, propyl, isopropyl,t-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino,—N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂ and —OCF₃; or R² and R³ taken togetherwith the nitrogen atom to which they are attached form Ring A which isazetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl,each optionally substituted with at least one R¹⁰ substituent selectedfrom methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br,CN, —N(CH₃)₂, hydroxyl, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and whereineach ring is further optionally fused with Y which is phenyl; R⁵ is H,methyl, ethyl, propyl or isopropyl; R⁶ is H; C₁-C₆alkyl or C₁-C₆alkoxyeach optionally substituted with at least one hydroxy; C₁-C₆haloalkyl,—OCF₃, —C(O)NR^(a)R⁸, —R^(c)S(O)_(p)R⁸, —R^(c)NR^(a)R^(b), —R^(c)OR^(a),—S(O)_(p)R⁸; phenyl, C₁alkylphenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl,oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, tetrahydrofuranyl, C₁-C₂alkyloxazolidinyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, C₁-C₂tetrahydrofuranyl,pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,C₁-C₂alkylpyrazolyl, C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl,C₁-C₂alkylpyrimidinyl or C₁-C₂alkylpyrazinyl; and wherein the phenyl,cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent eachindependently selected from methyl, ethyl, methoxy, ethoxy, —CHF₂, —CF₃,—OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy; or R⁵ andR⁶ taken together with the nitrogen atom to which they are attached formRing B which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl, each of which is optionally substituted with at leastone R⁹ substituent selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH₃)₂, hydroxy, —CHF₂, —CF₃,—OCHF₂, —OCF₃ and oxo; and wherein each ring is further optionally fusedwith Y which is phenyl, pyridinyl or pyrimidinyl; and R⁸ is methyl,ethyl; or cyclopropyl or phenyl each optionally substituted with atleast one substituent selected from C₁-C₄alkyl, halogen, C₁-C₄alkoxy,—CF₃ and —OCF₃; stereoisomers thereof, and pharmaceutically acceptablesalts thereof.
 4. A Formula (1-A1) compound

wherein R^(a), R^(b) and R⁰ are each independently H, methyl, ethyl orpropyl; R^(c) is methyl, ethyl or propyl; R¹ is methyl, ethyl, propyl,isopropyl; or R¹ is benzyl, —CH₂pyridine, —CH₂pyrimidine, —CH₂pyrazoleor —CH₂imidazole, each optionally substituted with at least one R⁹substituent selected from methyl, ethyl, methoxy, ethoxy, F, Cl,hydroxy, —CF₃ and —OCF₃; R² and R³ are each independently H, C₁-C₆alkyl,—CH₂N(CH₃)₂, —CH₂CH₂N(CH₃)₂; or C₀-C₂cyclopropyl, C₀-C₂cyclobutyl,C₀-C₂cyclopentyl, C₀-C₂cyclohexyl, C₀-C₂phenyl, C₀-C₂piperadinyl,piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which isoptionally substituted with at least one R⁹ substituent; R⁵ and R⁶ areeach independently H; C₁-C₆alkyl or C₁-C₆alkoxy each optionallysubstituted with at least one hydroxy; cyano, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, —C(O)R⁸, —C(O)NR^(a)R⁸, —C(O)R^(c)NR^(a)R^(b),—C(O)OR^(c)R⁸, —C(O)ONR^(a)R^(b), —R^(c)NR^(a)C(O)R⁸, —R^(c)C(O)OH,—R^(c)C(O)NR^(a)R^(b), —R^(c)NR^(a)C(O)H, —R^(c)S(O)_(p)R⁸,—R^(c)NR^(a)R^(b), —R^(c)OR^(a), —S(O)_(p)R⁸, —S(O)_(p)R⁸NR^(a)R^(b),—R^(c)S(O)_(p)NR^(a)R^(b), and —R^(c)NR^(a)S(O)_(p)R⁸; phenyl,C₁alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl, C₁-C₂alkylcyclopentyl,C₁-C₂alkylcyclohexyl, tetrahydrofuranyl, tetrahydropyranyl,oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,C₁-C₂alkyltetrahydrofuranyl, C₁-C₂alkyloxazolidinyl,C₁-C₂alkyltetrahydropyranyl, C₁-C₂alkylpyrrolidinyl,C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl, C₁-C₂morpholinyl;pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkyltriazolyl, C₁-C₂alkyltetrazolyl,C₁-C₂alkyloxazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyridazinyl,C₁-C₂alkylpyrimidinyl, and C₁-C₂alkylpyrazinyl; and wherein the phenyl,cycloalkyl ring, heterocycle ring and heteroaryl ring are eachoptionally substituted with at least one R¹⁰ substituent; R⁸ is methyl,ethyl; or cyclopropyl or phenyl each optionally substituted with atleast one substituent selected from C₁-C₄alkyl, halogen, C₁-C₄alkoxy,—CF₃ and —OCF₃; R⁹ is selected from the group consisting of methyl,ethyl, propyl, isopropyl, t-butyl, methoxy, ethoxy, F, Cl, Br, cyano,—N(CH₃)₂, —CHF₂, —CF₃, —OCHF₂, and —OCF₃; and R¹⁰ is independentlyselected from methyl, ethyl, propyl, methoxy, ethoxy, —CHF₂, —CF₃,—OCF₃, F, Cl, —NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, nitro, cyano; stereoisomersthereof, and pharmaceutically acceptable salts thereof.
 5. A compound ofclaim 4 that is a Table H compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof.
 6. A compound of claim 4,wherein R⁰ is each independently H, methyl or propyl; R¹ is methyl,ethyl, propyl, isopropyl; or R¹ is benzyl optionally substituted with atleast one R⁹ substituent selected from methyl, ethyl, methoxy, ethoxy,F, Cl, hydroxy, —CF₃ and —OCF₃; R² is H, methyl, ethyl or isopropyl; R³is H, methyl, ethyl, propyl, isopropyl, t-butyl; —CH₂N(CH₃)₂,—CH₂CH₂N(CH₃)₂, cyclopropyl or cyclobutyl; or phenyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted withat least one R⁹ substituent selected from the group consisting ofmethyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino,cyclopropyl and —CF₃; R⁵ is H; R⁶ is H or C₁-C₆alkyl; stereoisomersthereof, and pharmaceutically acceptable salts thereof.
 7. A compound ofclaim 6 that is selected from the group consisting of:1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;1-ethyl-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-phenylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-isopropyl-1-methyl-3-phenylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((butylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-2-yl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrazin-2-yl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridazin-3-yl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-5-yl)urea;1-(5-chloropyrimidin-2-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea;1-(5-cyclopropylpyrimidin-2-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-3-yl)urea;1-(2,6-dimethylpyrimidin-4-yl)-3-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-4-yl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(3-methylpyridin-4-yl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-3-phenyl-1-propylurea;3-(4-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;3-(3-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;3-(2-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(o-tolyl)urea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-fluorophenyl)-1-methylurea;3-(4-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-fluorophenyl)-1-methylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-methoxyphenyl)-1-methylurea;3-(3-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopropylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclobutylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)phenyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;3-(2-(dimethylamino)ethyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;and1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;stereoisomers thereof, and pharmaceutically acceptable salts thereof. 8.A compound of claim 7 that is1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;stereoisomers thereof, and pharmaceutically acceptable salts thereof. 9.A compound of claim 1, wherein W is H that is a Formula (1.1) compound

wherein R⁰, R¹ and R² are each independently H or C₁-C₆alkyl; and R³ ispyrazole; phenyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, eachoptionally substituted with at least one R⁹ substituent selected fromthe group consisting of methoxy, cyano, —CF₃, F, Cl and methyl;stereoisomers thereof and pharmaceutically acceptable salts thereof. 10.A compound of claim 1, that is a Formula (1-A0), Formula (1-A2), Formula(1-A3), Formula (1-A4), Formula (1-A5) or Formula (1-A6) compound,

wherein: X′ is F, Cl or Br; R⁰ is H, methyl, ethyl or propyl; R^(a) isH, methyl or ethyl; R¹ is H or methyl; R² is H, methyl, ethyl,cyclopropyl or phenyl; R³ is H, methyl, ethyl or propyl; or cyclopropyl,cyclobutyl, phenyl, C₁phenyl, piperadinyl, C₁-piperadinyl, piperazinyl,morpholinyl or pyridinyl, and wherein each ring is optionallysubstituted with at least one R⁹ substituent selected from the groupconsisting of methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, —N(CH₃)₂ and—CF₃; and R⁷ is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH₂NH₂,—CH₂NHCH₃ or —CH₂N(CH₃)₂; stereoisomers thereof, and pharmaceuticallyacceptable salts thereof.
 11. A compound of claim 10 that is anon-antibacterial Formula (1-A0) Table B compound; a Formula (1-A2)Table C compound; a non-antibacterial Formula (1-A3) Table D compound; aFormula (1-A4) Table E compound; a non-antibacterial Formula (1-A5)Table F compound; or a Formula (1-A6) Table G compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof.
 12. A compoundof Formula (1-A1) of claim 3, that is a Formula (1-A1a) compound

wherein R⁰ is H, methyl or propyl; R⁵ is H, methyl, ethyl, propyl orisopropyl; R⁶ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, methoxy, ethoxy, —CH₂CF₃, —CF₃, —OCF₃; —C(O)NR^(a)R⁸ whereinR^(a) is H or methyl and R⁸ is H, methyl, cyclopropyl, phenyl optionallysubstituted with F, Cl or —CF₃; —(CH₂)S(O)₂R⁸ wherein R⁸ is methyl orphenyl; —CH₂NR^(a)R^(b) or —(CH₂)₂NR^(a)R^(b) wherein R^(a) and R^(b)are each independently H or methyl; —(CH₂)₂OCH₃, —(CH₂)₃OCH₃; phenyl,C₁alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,C₁-C₂alkylcyclopropyl, C₁-C₂alkylcyclobutyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,C₁-C₂alkylpyrrolidinyl, C₁-C₂alkylpiperidinyl, C₁-C₂alkylpiperazinyl,C₁-C₂morpholinyl, C₁-C₂tetrahydropyranyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, C₁-C₂alkylpyrazolyl,C₁-C₂alkylimidazolyl, C₁-C₂alkylpyridinyl, C₁-C₂alkylpyrimidinyl orC₁-C₂alkylpyrazinyl; and wherein the phenyl, cycloalkyl ring,heterocycle ring and heteroaryl ring are each optionally substitutedwith at least one R¹⁰ substituent each independently selected frommethyl, ethyl, methoxy, ethoxy, F, Cl, amino, —CF₃, —CHF₂, —OCF₃,—NHCH₃, —N(CH₃)₂, —S(O)₂CH₃, cyano and hydroxy; Ring A is pyrrolyl,pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl; andwherein each ring is further optionally fused with Y which is phenyl;stereoisomers thereof, and pharmaceutically acceptable salts thereof.13. A compound of Formula (1-A1) of claim 3, that is a Formula (1-A1b)compound

wherein R⁰ is H, methyl, ethyl or propyl; R² is H or methyl; R³ ismethyl, ethyl or propyl; or cyclopropyl, cyclobutyl, phenyl, C₁phenyl,piperadinyl, C₁-piperadinyl, piperazinyl, morpholinyl or pyridinyl, andwherein each ring is optionally substituted with at least one R⁹substituent selected from the group consisting of methyl, ethyl,methoxy, ethoxy, F, Cl, cyano, —N(CH₃)₂ and —CF₃; Ring B which ispyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, eachoptionally substituted with at least one R⁹ substituent selected frommethyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN,—N(CH₃)₂, hydroxy, —CHF₂, —CF₃, —OCHF₂, —OCF₃ and oxo; and wherein eachring is further optionally fused with Y which is phenyl; each optionallysubstituted with at least one R¹⁰ substituent selected from methyl,ethyl, methoxy, halogen, cyano, hydroxy and oxo; stereoisomers thereof,and pharmaceutically acceptable salts thereof.
 14. A Formula (1-A1)compound of claim 3 that is a non-antibacterial Table I compound or anon-antibacterial Table J compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof.
 15. A composition comprisinga compound of claim 1, and wherein the composition further comprises apharmaceutically acceptable carrier.
 16. A composition comprising acompound of claim 7, and wherein the composition further comprises apharmaceutically acceptable salt thereof.
 17. A composition comprising1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;stereoisomers thereof, and pharmaceutically acceptable salts thereof andwherein the composition further comprises a pharmaceutically acceptablecarrier.
 18. A method of treating or preventing an inflammatory responsein an animal by administering to said animal in need thereof, atherapeutically effective amount of a compound of claim 1, stereoisomersthereof, and pharmaceutically acceptable salts thereof.
 19. A method oftreating or preventing an inflammatory response in an animal byadministering to said animal in need thereof, a therapeuticallyeffective amount of the compound of claim 4 stereoisomers thereof, andpharmaceutically acceptable salts thereof.
 20. A method of treating orpreventing an inflammatory response in an animal by administering tosaid animal in need thereof, a therapeutically effective amount of thecompound of claim 8 that is1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;stereoisomers thereof, and pharmaceutically acceptable salts thereof.